D-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides having immunosuppressive activity

ABSTRACT

O-Heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides of the general structural Formula I: ##STR1## have been prepared from suitable precursors by alkylation and/or arylation at C-3&#34; and/or C-4&#34; of the cyclohexyl ring. These macrolide immunosuppressants are useful in a mammalian host for the treatment of autoimmune diseases, infectious diseases, the prevention of rejection of foreign organ transplants and/or related afflictions, diseases and illnesses.

SUMMARY OF THE INVENTION

This application is a continuation-in-part of copending application Ser.No. 07/756,946, filed Sep. 9, 1991, now abandoned.

The present invention is related to O-heteroaryl, O-alkylheteroaryl,O-alkenylheteroaryl and O-alkynylheteroarylmacrolides which are usefulin a mammalian host for the treatment of autoimmune diseases (such asjuvenile-onset diabetes mellitus, multiple sclerosis and rheumatoidarthritis), immunodepression, infectious diseases and/or the preventionof rejection of foreign organ transplants (e.g. bone marrow and hearttransplants and xeno transplants) and are also useful in the topicaltreatment of inflammatory and hyperproliferative skin diseases andcutaneous manifestations of immunologically-mediated illnesses (such as:psoriasis, atopical dermatitis, contact dermatitis and furthereczematous dermatitises, seborrhoeic dermatitis, Lichen planus,Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria,angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupuserythematosus, Alopecia areata), male pattern alopecia, alopeciasenilis, reversible obstructive airways disease, particularly asthma,alopecia, inflammation of mucosa and blood vessels, cytomegalovirusinfection, multidrug resistance, idiopathic thrombocytopenic purpura,Behcet's syndrome, conjunctivitis, Crohn's disease, Mooren's ulcer,uveitis, severe intraocular inflammation, and/or hepatic injuryassociated with ischemia. In addition, some of the compounds of thisinvention may have antagonistic properties and so have utility in thereversal of immunosuppressive activity and/or diminishing the toxicityof other immunosuppressive agents.

More particularly, this invention relates to compounds of the generalstructural formula I: ##STR2## wherein R¹, R², R³, R⁴, R⁵, R¹⁰, W and nare hereinafter defined.

This invention also relates to pharmaceutical compositions containingthe compounds and to a method of use of the present compounds and otheragents for the treatment of and prevention of certain afflictions,diseases and illnesses.

BRIEF DESCRIPTION OF DISCLOSURES IN THE ART

Fujisawa United States, European and Japanese patents and applications(U.S. Pat. No. 4,894,366, issued Jan. 16, 1990, EPO Publication No.0,184,162 and PBJ Disclosure 63-17884) and publications (J. Am. Chem.Soc., 1987, 109, 5031 and J. Antibiotics 1987, 40, 1249) disclose17-allyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (FR-900506), (FK-506), (L-679,934),17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (FR-900520) and related compoundswhich are the starting materials for the preparation of the compoundsdescribed. The synthetic preparation of the aforementioned startingmaterial (FR-900506) has recently been reported (J. Am. Chem. Soc.,1989, 111, 1157). A Sandoz European patent application (EPO PublicationNo. 0,356,399) discloses stereoisomers of FR-900506 and derivatives atthe 17-position. Fisons European and WIPO patent applications (EPOPublication No. 0,323,042 and PCT Publication No. WO 89/05304) disclosesvarious derivatives of FR-900506, FR-900520 and related compounds. ASandoz European Patent application (EPO Publication No. 0,437,680)discloses chloro, bromo, iodo and azido derivatives of FR-900506,FR-900520 and related compounds. A Merck European Patent application(EPO Publication No. 0,428,365) discloses various amino derivatives ofFR-900506, FR-900520 and related compounds. A Fujisawa patentapplication (UK Publication No. GB 2,245,891-A) discloses variousderivatives of FR-900506 bearing a heterocyclic group.

Fujisawa United States patents (U.S. Pat. No. 4,929,611, issued May 29,1990, U.S. Pat. No. 4,956,352, issued Sep. 11, 1990 and U.S. Pat. No.5,110,811, issued May 5, 1992) discloses the use of FK-506-typecompounds in treating resistance to transplantation. A Sandoz Europeanpatent application (EPO Publication No. 0,315,978) discloses the use ofFR-900506 and related compounds in the topical treatment of inflammatoryand hyperproliferative skin diseases and of cutaneous manifestations ofimmunologically-mediated illness. A Fisons WIPO patent application (PCTPublication No. WO 91/04025) discloses the use of various derivatives ofFR-900506 in the treatment of immunodepression. A Fisons WIPO patentapplication (PCT Publication WO 90/14826) discloses the use of FR-900506and related compounds in the treatment of reversible obstructive airwaysdisease, particularly asthma. A Fujisawa European patent application(EPO Publication No. 0,423,714) discloses the use of FK-506 andderivatives as hair revitalizing agents. Various studies have suggestedthe efficacy of FK-506 in the treatment of a number of ailments,including rheumatoid arthritis (C. Arita, et al., Clinical exp.Immunol., 1990, 82, 456-461; N. Inamura, et al., Clin. Immunol.Immunopathol. 1988, 46, 82-90), recent-onset diabetes (N. Murase, etal., Diabetes, 1990, 39, 1584-86; N. Murase, et al., Lancet, 1990, 336,373-74), posterior uveitis (H. Kawashima, Invest. Ophthalmol. Vis. Sci.,1988, 29, 1265-71), hepatic injury associated with ischemia (M. Sakr, etal., Life Sci., 1990, 47, 687-91) allergic encephalomyelitis (K,Deguchi, et al., Brain Nerve, 1990, 42, 391-97), glomerulonephritis (J.McCauley, et al., Lancet, 1990, 335, 674) and systemic lupuserythematosus (K. Takabayashi, et al., Clin. Immunol. Immunopathol.,1989, 51, 110-117) multidrug resistance (M. Naito, et al., CancerChemother. Pharmacol., 1992, 29, 195-200), inflammation of mucosa andblood vessels (PCT Publication WO 91/17754), cytomegalovirus infection(UK Publication GB 2,247,620A), and idiopathic thrombocytophenic purpuraand Basedow's disease (PCT Publication WO 91/19495).

BACKGROUND OF THE INVENTION

Immunoregulatory abnormalities have been shown to exist in a widevariety of "autoimmune" and chronic inflammatory diseases, includingsystemic lupus erythematosis, chronic rheumatoid arthritis, type I andII diabetes mellitus, inflammatory bowel disease, biliary cirrhosis,uveitis, multiple sclerosis and other disorders such as Crohn's disease,ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis,ichthyosis, and Graves ophthalmopathy. Although the underlyingpathogenesis of each of these conditions may be quite different, theyhave in common the appearance of a variety of autoantibodies andself-reactive lymphocytes. Such self-reactivity may be due, in part, toa loss of the homeostatic controls under which the normal immune systemoperates.

Similarly, following a bone-marrow or an organ transplantation, the hostlymphocytes recognize the foreign tissue antigens and begin to produceantibodies which lead to graft rejection.

One end result of an autoimmune or a rejection process is tissuedestruction caused by inflammatory cells and the mediators they release.Antiinflammatory agents such as NSAID's and corticosteroids actprincipally by blocking the effect or secretion of these mediators butdo nothing to modify the immunologic basis of the disease. On the otherhand, cytotoxic agents such as cyclophosphamide, act in such anonspecific fashion that both the normal and autoimmune responses areshut off. Indeed, patients treated with such nonspecificimmunosuppressive agents are as likely to succumb from infection as theyare from their autoimmune disease.

Cyclosporin A which was approved by the US FDA in 1983 is currently theleading drug used to prevent rejection of transplanted organs. The drugacts by inhibiting the body's immune system from mobilizing its vastarsenal of natural protecting agents to reject the transplant's foreignprotein. Though cyclosporin A is effective in fighting transplantrejection, it is nephrotoxic and is known to cause several undesirableside effects including kidney failure, abnormal liver function andgastrointestinal discomfort.

Newer, safer drugs exhibiting less side effects are constantly beingsearched for in the field.

The 23-membered tricyclo-macrolide immunosuppressant, tacrolimus,FR-900506, FK-506, ##STR3##

(17-allyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone) and related compounds which wereisolated and characterized by Tanaka, Kuroda, and co-workers at FujisawaPharmaceutical Co. in Japan, see J. Am. Chem. Soc., 1987, 109, 5031, andU.S. Pat. No. 4,894,366, issued Jan. 16, 1990) have been shown topossess exceptional immunosuppressive activity. Fujisawa United Statespatents (U.S. Pat. No. 4,929,611, issued May 29, 1990, U.S. Pat. No.4,956,352, issued Sep. 11, 1990 and U.S. Pat. No. 5,110,811, issued May5, 1992) disclose the use of FK-506-type compounds in treatingresistance to transplantation. In particular, the compound FR-900506 hasbeen reported to be 100 times more effective than cyclosporin in thesuppression of in vitro immune systems (J. Antibiotics 1987, 40, 1256).In addition, these compounds are reputed to possess topical activity inthe treatment of inflammatory and hyperproliferative skin diseases andcutaneous manifestations of immunologically-mediated illnesses (EPO Pub.No. 0,315,978).

The compound FK-506 and related compounds further have been suggested tobe useful in the treatment of obstructive airways disease, particularlyasthma (PCT Publication WO 90/14826), male pattern alopecia or alopeciasenilis (EPO Publication No. 0,423,714), rheumatoid arthritis (C. Arita,et al., Clincial exp. Immunol., 1990, 82, 456-461; N. Inamura, et al.,Clin. Immunol. Immunopathol. 1988, 46, 82-90), recent-onset diabetes (N.Murase, et al., Diabetes, 1990, 39, 1584-86; N. Murase, et al., Lancet,1990, 336, 373-74), posterior uveitis (H. Kawashima, Invest. Ophthalmol.Vis. Sci., 1988, 29, 1265-71), hepatic injury associated with ischemia(M. Sakr, et al., Life Sci., 1990, 47, 687-91) allergicencephalomyelitis (K, Deguchi, et al., Brain Nerve, 1990, 42, 391-97),glomerulonephritis (J. McCauley, et al., Lancet, 1990, 335, 674),systemic lupus erythematosus (K. Takabayashi, et al., Clin. Immunol.Immunopathol., 1989, 51, 110-117) multidrug resistance (M. Naito, etal., Cancer Chemother. Pharmacol., 1992, 29, 195-200), inflammation ofmucosa and blood vessels (PCT Publication WO 92/17754), cytomegalovirusinfection (UK Publication GB 2,247,620A), and idiopathicthrombocytophenic purpura and Basedow's disease (PCT Publication WO91/19495).

DETAILED DESCRIPTION OF THE INVENTION A. Scope of the Invention

The novel compound of this invention has structural Formula I: ##STR4##or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom:

(1) heteroaryl;

(2) substituted heteroaryl in which the substituents are X, Y and Z;

(3) heteroaryl-C₁₋₁₀ alkyl;

(4) substituted heteroaryl-C₁₋₁₀ alkyl in which the heteroaryl group issubstituted by X, Y and Z and the alkyl portion may be substituted withone or more of the substituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ -alkoxy,

(d) aryl-C₁₋₃ alkoxy,

(e) substituted aryl-C₁₋₃ alkoxy, in which the substituents on aryl areX, Y and Z,

(f) unsubstituted or substituted aryloxy, in which the substituents onaryl are X, Y and Z,

(g) --OCO--C₁₋₆ alkyl,

(h) --NR⁶ R⁷, wherein R⁶ and R⁷ are independently selected from

(i) hydrogen,

(ii) C₁₋₁₀ alkyl unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a') aryl, which is unsubstituted or substituted with X, Y and Z,

(b') heteroaryl, which is unsubstituted or substituted with X, Y and Z,

(c') --OH,

(d') C₁₋₆ alkoxy,

(e') --CO₂ H,

(f') --CO₂ --C₁₋₆ alkyl,

(g') --C₃₋₇ cycloalkyl, and

(h') --OR¹¹,

(iii) C₃₋₁₀ alkenyl unsubstituted or substituted with one or more of thesubstituent(s) selected from:

(a') aryl, which is unsubstituted or substituted with X, Y and Z,

(b') heteroaryl, which is unsubstituted or substituted with X, Y and Z,

(c') --OH,

(d') C₁₋₆ alkoxy,

(e') --CO₂ H,

(f') --CO₂ --C₁₋₆ alkyl,

(g') --C₃₋₇ cycloalkyl, and

(h') --OR¹¹,

(iv) or where R⁶ and R⁷ and the N to which they are attached may form anunsubstituted or substituted 3-7-membered heterocyclic ring which mayinclude one or two additional heteroatoms independently selected fromthe group consisting of O, S(O)_(p), NR¹⁴, wherein R¹⁴ is hydrogen orC₁₋₆ alkyl unsubstituted or substituted by phenyl, and p is 0, 1 or 2,such as morpholine, thiomorpholine, piperidine, or piperizine,

(i) --NR⁶ CO--C₁₋₆ alkyl-R⁷, wherein R⁶ and R⁷ are as defined above,

(j) --NR⁶ CO₂ --C₁₋₆ alkyl--R⁷,

(k) --NR⁶ CONR⁶ R⁷,

(l) --OCONR⁶ R⁷,

(m) --COOR⁶,

(n) --CHO,

(o) aryl,

(p) substituted aryl in which the substituents are X, Y and Z,

(q) --OR¹¹, and

(r) --S(O)_(p) --C₁₋₆ alkyl;

(5) heteroaryl-C₁₋₁₀ alkyl wherein one or more of the alkyl carbons isreplaced by a group selected from: --NR⁶ --, --O--, --S(O)_(p) --, --CO₂--, --O₂ C--, --CONR⁶ --, --NR⁶ CO--, --NR⁶ CONR⁷ --;

(6) substituted heteroaryl-C₁₋₁₀ alkyl wherein one or more of the alkylcarbons is replaced by a group selected from: --NR⁶ --, --O--,--S(O)_(p) --, --CO₂ --, --O₂ C--, --CONR⁶ --, and --NR⁶ CONR⁷ --, theheteroaryl group is substituted with X, Y, and Z, and the alkyl groupmay be substituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) aryl-C₁₋₃ alkoxy,

(e) substituted aryl-C₁₋₃ alkoxy, in which the substituents on aryl areX, Y and Z,

(f) unsubstituted or substituted aryloxy, in which the substituents onaryl are X, Y and Z,

(g) --OCO--C₁₋₆ alkyl,

(h) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(i) --NR⁶ CO--C₁₋₆ alkyl-R⁷,

(j) --NR⁶ CO₂ --C₁₋₆ alkyl-R⁷,

(k) --NR⁶ CONR⁶ R⁷,

(l) --OCONR⁶ R⁷,

(m) --COOR⁶,

(n) --CHO,

(o) aryl,

(p) substituted aryl in which the substituents are X, Y and Z,

(q) --OR¹¹, and

(r) --S(O)_(p) --C₁₋₆ alkyl;

(7) heteroaryl-C₃₋₁₀ alkenyl wherein alkenyl contains one to four doublebonds;

(8) heteroaryl-C₃₋₁₀ alkenyl wherein alkenyl contains one to four doublebonds and wherein one or more of the alkyl carbons is replaced by agroup selected from: --NR⁶ --, --O--, --S(O)_(p) --, --CO₂ --, --O₂ C--,--CONR⁶ --, --NR⁶ CO--, and --NR⁶ CONR⁷ --;

(9) substituted heteroaryl-C₃₋₁₀ alkenyl wherein alkenyl contains one tofour double bonds and wherein one or more of the alkyl carbons may bereplaced by a group selected from: --NR⁶ --, --O--, --S(O)_(p) --, --CO₂--, --O₂ C--, --CONR⁶ --, --NR⁶ CO--, and --NR⁶ CONR⁷, the heteroarylgroup is substituted with X, Y, and Z, and the alkyl group may besubstituted with one or more of the substituent(s) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) aryl-C₁₋₃ alkoxy,

(e) substituted aryl-C₁₋₃ alkoxy, in which the substituents on aryl areX, Y and Z,

(f) unsubstituted or substituted aryloxy, in which the substituents onaryl are X, Y and Z,

(g) --OCO--C₁₋₆ alkyl,

(h) --NR⁶ R⁷, wherein R⁶ and R⁷ as defined above,

(i) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above,

(j) --NR⁶ CO₂ --C₁₋₆ alkyl,

(k) --NR⁶ CONR⁶ R⁷,

(l) --OCONR⁶ R⁷,

(m) --COOR⁶,

(n) --CHO,

(o) aryl,

(p) substituted aryl in which the substituents are X, Y and Z, and

(q) --OR¹¹, and

(r) --S(O)_(p) --C₁₋₆ alkyl;

R² is selected from:

(1) the definitions of R¹ ;

(2) hydrogen;

(3) phenyl;

(4) substituted phenyl in which the substituents are X, Y and Z;

(5) 1- or 2-naphthyl;

(6) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ;

(7) biphenyl;

(8) substituted biphenyl in which the substituents are X, Y and Z;

(9) C₁₋₁₀ alkyl;

(10) substituted-C₁₋₁₀ alkyl in which one or more substituent(s) is(are)selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) aryl-C₁₋₃ alkoxy,

(e) substituted aryl-C₁₋₃ alkoxy, in which the substituents on aryl areX, Y and Z,

(f) unsubstituted or substituted aryloxy, in which the substituents onaryl are X, Y and Z,

(g) --OCO--C₁₋₆ alkyl,

(h) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above

(i) --NR⁶ CO--C₁₋₆ alkyl-R⁷, wherein R⁶ and R⁷ are as defined above,

(j) --COOR⁶, wherein R⁶ is as defined above,

(k) --CHO,

(l) phenyl,

(m) substituted phenyl in which the substituents are X, Y and Z,

(n) 1- or 2-naphthyl,

(o) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(p) biphenyl,

(q) substituted biphenyl in which the substituents are X, Y and Z,

(r) --OR¹¹, and

(s) --S(O)_(p) --C₁₋₆ alkyl;

(11) C₃₋₁₀ alkenyl;

(12) substituted C₃₋₁₀ alkenyl in which one or more substituent(s)is(are) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above

(h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above,

(i) --COOR⁶, wherein R⁶ is as defined above,

(j) --CHO,

(k) phenyl,

(l) substituted phenyl in which the substituents are X, Y and Z,

(m) 1- or 2-naphthyl,

(n) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(o) biphenyl,

(p) substituted biphenyl in which the substituents are X, Y and Z,

(q) --OR¹¹, and

(r) --S(O)_(p) --C₁₋₆ alkyl;

(13) C₃₋₁₀ alkynyl;

(14) substituted C₃₋₁₀ alkynyl in which one or more substituent(s)is(are) selected from:

(a) hydroxy,

(b) oxo,

(c) C₁₋₆ alkoxy,

(d) phenyl-C₁₋₃ alkoxy,

(e) substituted phenyl-C₁₋₃ alkoxy, in which the substituents on phenylare X, Y and Z,

(f) --OCO--C₁₋₆ alkyl,

(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above,

(i) --COOR⁶, wherein R⁶ is as defined above,

(j) --CHO,

(k) phenyl,

(l) substituted phenyl in which the substituents are X, Y and Z,

(m) 1- or 2-naphthyl,

(n) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ,

(o) biphenyl,

(p) substituted biphenyl in which the substituents are X, Y and Z,

(q) --OR¹¹ ; and

(15) --R¹¹ ;

R³ is hydrogen, hydroxy, --OR¹¹, or C₁₋₆ alkoxy;

R⁴ is hydrogen, or R³ and R⁴ taken together form a double bond;

R⁵ is methyl, ethyl, propyl or allyl;

R¹⁰ is hydrogen, hydroxy, --OR¹¹ or fluoro;

R¹¹ is selected from:

(a) --PO(OH)O⁻ M⁺, wherein M⁺ is a positively charged inorganic ororganic counterion,

(b) --SO₃ ⁻ M⁺,

(c) --CO(CH₂)_(q) CO₂ ⁻ M⁺, wherein q is 1-3, and

(d) --CO--C₁₋₆ alkyl-NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above andthe alkyl is unsubstituted or substituted with one or more substituentsselected from:

(i) hydroxy,

(ii) C₁₋₆ alkoxy,

(iii) --NR¹⁶ R¹⁷, wherein R¹⁶ and R¹⁷ are independently selected from:

(a') hydrogen, and

(b') C₁₋₆ alkyl,

(iv) --COOR⁶, wherein R⁶ is as defined above,

(v) phenyl,

(iv) substituted phenyl in which the substituents are X, Y and Z,

(vii) heteroaryl,

(viii) --SH, and

(ix) --S--C₁₋₆ alkyl;

W is O or (H, OH);

X, Y and Z independently are selected from:

(a) hydrogen,

(b) C₁₋₁₀ alkyl, unsubstituted or substituted with one or moresubstituents selected from:

(i) aryl,

(ii) substituted aryl in which the substituents are X', Y' and Z',

(iii) heteroaryl,

(iv) substituted heteroaryl in which the substituents are X', Y', andZ',

(v) unsubstituted or substituted aryloxy, in which the substituents onaryl are X', Y' and Z',

(vi) --OR⁶,

(vii) --OR¹¹,

(viii) --OCOR⁶,

(ix) --OCO₂ R⁶,

(x) --NR⁶ R⁷,

(xi) --CHO,

(xii) --NR⁶ COC₁₋₆ alkyl-R⁷,

(xiii) --NR⁶ CO₂ C₁₋₆ alkyl-R⁷,

(xiv) --NR⁶ CONR⁶ R⁷,

(xv) --OCONR⁶ R⁷,

(xvi) --CONR⁶ R⁷,

(c) C₁₋₁₀ alkyl wherein one or more of the alkyl carbons is replaced bya group selected from --NR⁶ --, --O--, --S(O)_(p) --, --CO₂ --, --O₂C--, --CONR⁶ --, --NR⁶ CO--, --NR⁶ CONR⁷ --, --CO--, --CH(OH)--, alkenylor alkynyl and the alkyl may be unsubstituted or substituted with one ormore substituents selected from:

(i) aryl,

(ii) substituted aryl in which the substituents are X', Y' and Z',

(iii) heteroaryl,

(iv) substituted heteroaryl in which the substituents are X', Y', andZ',

(v) unsubstituted or substituted aryloxy, in which the substituents onaryl are X', Y', and Z',

(vi) --OR⁶,

(vii) --OR¹¹,

(viii) --OCOR⁶,

(ix) --OCO₂ R⁶,

(x) --NR⁶ R⁷,

(xi) --CHO

(xii) --NR⁶ COC₁₋₆ alkyl-R⁷,

(xiii) --NR⁶ CO₂ C₁₋₆ alkyl-R⁷,

(xiv) --NR⁶ CONR⁶ R⁷,

(xv) --OCONR⁶ R⁷,

(xvi) --CONR⁶ R⁷,

(d) halogen,

(e) --NR⁶ R⁷,

(f) --CN,

(g) --CHO,

(h) --CF₃,

(i) --SR⁸, wherein R⁸ is hydrogen, C₁₋₆ alkyl, trifluoromethyl, orphenyl,

(j) --SOR⁸,

(k) --SO₂ R⁸,

(l) --CONR⁶ R⁷,

(m) R⁹ O(CH₂)_(m) -- wherein R⁹ is hydrogen, C₁₋₆ alkyl, hydroxy-C₂₋₃alkyl, --CF₃, phenyl, R¹¹ or naphthyl and m is 0, 1, 2, or 3,

(n) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are C₁₋₃ alkyl or takentogether form an ethyl or propyl bridge,

(o) ##STR5## wherein R⁹ and m are as defined above, (p) ##STR6## whereinR⁹ and m are as defined above, and (q) --R¹¹ ;

or any two of X, Y and Z may be joined to form a saturated ring having5, 6 or 7 ring atoms, said ring atoms comprising 1 or 2 oxygen atoms,the remaining ring atoms being carbon, such as dioxolanyl or dioxanyl;

X', Y' and Z' independently are selected from:

(a) hydrogen,

(b) C₁₋₇ alkyl,

(c) C₂₋₆ alkenyl,

(d) halogen,

(e) --(CH₂)_(m) --NR⁶ R⁷, wherein R⁶, R⁷, and m are as defined above,

(f) --CN,

(g) --CHO,

(h) --CF₃,

(i) --SR⁸, wherein R⁸ is hydrogen, C₁₋₆ alkyl, trifluoromethyl, orphenyl,

(j) --SOR⁸, wherein R⁸ is as defined above,

(k) --SO₂ R⁸, wherein R⁸ is as defined above,

(l) --CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above,

(m) R⁹ O(CH₂)_(m) -- wherein R⁹ and m are as defined above,

(n) --CH(OR¹²)(OR¹³), wherein R¹² and R¹³ are as defined above,

(o) ##STR7## wherein R⁹ and m are as defined above, (p) ##STR8## whereinR⁹ and m are as defined above, and (q) --R¹¹ ;

n is 1 or 2.

The compounds of the present invention have asymmetric centers and thisinvention includes all of the optical isomers and mixtures thereof.

In addition compounds with carbon-carbon double bonds may occur in Z-and E- forms with all isomeric forms of the compounds being included inthe present invention.

When any variable (e.g., alkyl, aryl, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, X, Y, Z,etc.) occurs more than one time in any variable or in Formula I, itsdefinition on each occurrence is independent of its definition at everyother occurrence.

As used herein, the term "alkyl" includes those alkyl groups of adesignated number of carbon atoms of either a straight, branched, orcyclic configuration. Examples of "alkyl" include methyl, ethyl, propyl,isopropyl, butyl, sec-and tert-butyl, pentyl, hexyl, heptyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,norbornyl, and the like. "Alkoxy" represents an alkyl group of indicatednumber of carbon atoms attached through an oxygen bridge, such asmethoxy, ethoxy, propoxy, butoxy and pentoxy. "Alkenyl" is intended toinclude hydrocarbon chains of a specified number of carbon atoms ofeither a straight- or branched-configuration and at least oneunsaturation, which may occur at any point along the chain, such asethenyl, propenyl, butenyl, pentenyl, dimethylpentyl, and the like, andincludes E and Z forms, where applicable; and "heteroarylalkyl"represents heteroaryl groups as herein defined which are attachedthrough a straight or branched chain alkyl group of from one to tencarbon atoms. "Halogen", as used herein, means fluoro, chloro, bromo andiodo.

As will be understood by those skilled in the art, pharmaceuticallyacceptable salts include, but are not limited to salts with inorganicacids such as hydrochloride, sulfate, phosphate, diphosphate,hydrobromide, and nitrate or salts with an organic acid such as malate,maleate, fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate or palmoate, salicylate andstearate. Similarly pharmaceutically acceptable cations include, but arenot limited to sodium, potassium, calcium, aluminum, lithium andammonium (especially ammonium salts with amines of the formula HNR⁶ R⁷).

The heteroaryl group as used herein includes acridine, carbazole,cinnoline, dibenzofuran, dibenzothiophene, quinoxaline, pyrrazole,indole, benzotriazole, furan, benzofuran, quinoline, isoquinoline,pyrazine, pyridazine, pyridine, pyrimidine, pyrrole which are optionallysubstituted.

In the compounds of Formula I the heteroaryl group may be optionallysubstituted with X, Y and Z at any available carbon atom or nitrogenatom (if present), but compounds bearing certain of X, Y and Z directlysubstituted to a nitrogen atom of the heteroaryl ring may be relativelyunstable and are not preferred.

The term "heteroaryl" as utilized herein is intended to include thefollowing heteraromatic groups which may include X, Y and Z substitutionas indicated and wherein Q is --N(X)--, --O--, --S--, --SO--, or --SO₂--: ##STR9##

The aryl or aromatic group may include phenyl or naphthyl which areoptionally substituted by from one- to three-members independentlyselected from the group consisting of: alkyl, alkenyl, halogen,carboxyl, CHO, amino, mono-alkylamino, di-alkylamino, aminoalkyl,mono-alkylaminoalkyl, di-alkylaminoalkyl, alkylthio, alkylsulfinyl,alkysulfonyl, trifluoromethyl, amido, mono-alkylamido, dialkylamido,hydroxy, hydroxyalkyl, R¹¹ O-alkyl, alkoxy, alkoxyalkyl, formamido,alkyl-CO₂ --, formamidoalkyl, alkyl-CO₂ -alkyl-, carboxyl, alkyl-CO₂ H,alkyl-O₂ C--, alkyl-O₂ C-alkyl-, and OR¹¹.

In the compound of formula I it is preferred that heteroaryl is selectedfrom the group consisting of: ##STR10## wherein X is as defined above.

In the compound of formula I it is also preferred that:

R² is selected from:

(1) hydrogen,

(2) methyl,

(3) ethyl,

(4) propyl,

(5) allyl,

(6) R¹¹,

(7) --C₂₋₃ alkyl-OH; and

(8) --C₂₋₃ alkyl-OR¹¹ ;

R³ is selected from:

(1) hydrogen,

(2) hydroxy,

(3) --OR¹¹, or

R³ and R⁴ taken together form a double bond;

R¹⁰ is hydrogen, hydroxy, fluoro, or --OR¹¹ ;

W is 0; and

n is 2.

In one embodiment of the present invention, heteroaryl is indole, whichmay be represented by: ##STR11## wherein X, Y and Z are as definedabove,

Preferred compounds of the present invention are the compoundsidentified as follows:

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-furanyl)methoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-furanyl)methoxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(2-furanyl)methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-thiophene)methoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-thiophene)methoxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3-thiophene)methoxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(2-thiophene)methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(3-thiophene)methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-thiophene)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethyoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-benzothienyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14,20-trihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,20-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1-hydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,20-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-allyoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)-oxy-3"-allyoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-n-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)-oxy-3"-n-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-i-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,20-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)-oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1-hydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)-oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

7-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,20-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1-hydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,20-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1-hydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-hydroxyethyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tertramethyl--11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,20-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)-oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1-hydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1-hydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-methoxy-N-tryptophanylcarbonylmethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4"-(3-indolyl)ethylaminocarbonylmethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-(3-hydroxypropyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-(1-hydroxyethylindol-5-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-hydroxyethylindol-6-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methylindol-6-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-dibenzylphosphonoxy-ethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

Monopotassium salt of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-phosphonoxy-ethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-(N,N-dimethylglycyloxy)ethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-succinyloxyethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,-10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methyl-3-phenylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methyl-3-(2-hydroxyethyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1,3-dimethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(9'-methylcarbazol-3'-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-diethylaminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-dimethylaminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-aminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-benzyloxycarbonyl-2'""-benzyloxycarbonylaminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(aspartyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(1'""-imidazolylcarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(1'""-piperazinocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(2'""-hydroxy)ethylaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(isopropyaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(1'""-piperidinocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(1'""-morpholinocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(diphenylaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(diethylaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-methanesulfonyloxyethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-azidoethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-aminoethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-t-butyldimethylsilyloxyethoxyethylindol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-hydroxyethoxyethylindol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octaxos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-methoxy-4"-(1'"-(1""-oxoprop-3""-yl)indol-5'"-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone; and

17-Ethyl-1,14-dihydroxy-12-[2'-(3"-methoxy-4"-(1'"-(1""-carboxyeth-2""-yl)indol-5'"-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone.

Representative compounds of the present invention include the compoundsof Formula X, XI, XII and XIII: ##STR12## wherein R^(6a) is H or CH₃ andthe definitions of R², R³, R⁵, R⁶ and R⁷ are selected from the followinggroups of substituents:

    ______________________________________                                        R.sup.6     R.sup.7       R.sup.2 R.sup.3                                                                            R.sup.5                                ______________________________________                                        phenyl      phenyl        CH.sub.3                                                                              OH   ethyl                                  phenyl      H             CH.sub.3                                                                              OH   ethyl                                  benzyl      H             CH.sub.3                                                                              OH   ethyl                                  4-HO.sub.2 C-benzyl                                                                       H             CH.sub.3                                                                              OH   ethyl                                  4-H.sub.2 NCO-benzyl                                                                      H             CH.sub.3                                                                              OH   ethyl                                  4-CH.sub.3 O-benzyl                                                                       H             CH.sub.3                                                                              OH   ethyl                                  4-HO-benzyl H             CH.sub.3                                                                              OH   ethyl                                  4-Cl-benzyl H             CH.sub.3                                                                              OH   ethyl                                  4-(CH.sub.3).sub.2 N-benzyl                                                               H             CH.sub.3                                                                              OH   ethyl                                  3-HO.sub.2 C-benzyl                                                                       H             CH.sub.3                                                                              OH   ethyl                                  3-H.sub.2 NCO-benzyl                                                                      H             CH.sub.3                                                                              OH   ethyl                                  3-CH.sub.3 O-benzyl                                                                       H             CH.sub.3                                                                              OH   ethyl                                  3-HO-benzyl H             CH.sub.3                                                                              OH   ethyl                                  3-Cl-benzyl H             CH.sub.3                                                                              OH   ethyl                                  3-(CH.sub.3).sub.2 N-benzyl                                                               H             CH.sub.3                                                                              OH   ethyl                                  4-pyridyl   H             CH.sub.3                                                                              OH   ethyl                                  3-pyridyl   H             CH.sub.3                                                                              OH   ethyl                                  2-pyridyl   H             CH.sub.3                                                                              OH   ethyl                                  4-pyridylmethyl                                                                           H             CH.sub.3                                                                              OH   ethyl                                  3-pyridylmethyl                                                                           H             CH.sub.3                                                                              OH   ethyl                                  2-pyridylmethyl                                                                           H             CH.sub.3                                                                              OH   ethyl                                  phenyl      phenyl        CH.sub.3                                                                              H    ethyl                                  phenyl      H             CH.sub.3                                                                              H    ethyl                                  benzyl      H             CH.sub.3                                                                              H    ethyl                                  4-HO.sub.2 C-benzyl                                                                       H             CH.sub.3                                                                              H    ethyl                                  4-H.sub.2 NCO-benzyl                                                                      H             CH.sub. 3                                                                             H    ethyl                                  4-CH.sub.3 O-benzyl                                                                       H             CH.sub.3                                                                              H    ethyl                                  4-HO-benzyl H             CH.sub.3                                                                              H    ethyl                                  4-Cl-benzyl H             CH.sub.3                                                                              H    ethyl                                  4-(CH.sub.3).sub.2 N-benzyl                                                               H             CH.sub.3                                                                              H    ethyl                                  3-HO.sub.2 C-benzyl                                                                       H             CH.sub.3                                                                              H    ethyl                                  3-H.sub.2 NCO-benzyl                                                                      H             CH.sub.3                                                                              H    ethyl                                  3-CH.sub.3 O-benzyl                                                                       H             CH.sub.3                                                                              H    ethyl                                  3-HO-benzyl H             CH.sub.3                                                                              H    ethyl                                  3-Cl-benzyl H             CH.sub.3                                                                              H    ethyl                                  3-(CH.sub.3).sub.2 N-benzyl                                                               H             CH.sub.3                                                                              H    ethyl                                  4-pyridyl   H             CH.sub.3                                                                              H    ethyl                                  3-pyridyl   H             CH.sub.3                                                                              H    ethyl                                  2-pyridyl   H             CH.sub.3                                                                              H    ethyl                                  4-pyridylmethyl                                                                           H             CH.sub.3                                                                              H    ethyl                                  3-pyridylmethyl                                                                           H             CH.sub.3                                                                              H    ethyl                                  2-pyridylmethyl                                                                           H             CH.sub.3                                                                              H    ethyl                                  phenyl      phenyl        CH.sub.3                                                                              OH   allyl                                  phenyl      H             CH.sub.3                                                                              OH   allyl                                  benzyl      H             CH.sub.3                                                                              OH   allyl                                  4-HO.sub.2 C-benzyl                                                                       H             CH.sub.3                                                                              OH   allyl                                  4-H.sub.2 NCO-benzyl                                                                      H             CH.sub.3                                                                              OH   allyl                                  4-CH.sub.3 O-benzyl                                                                       H             CH.sub.3                                                                              OH   allyl                                  4-HO-benzyl H             CH.sub.3                                                                              OH   allyl                                  4-Cl-benzyl H             CH.sub.3                                                                              OH   allyl                                  4-(CH.sub.3).sub.2 N-benzyl                                                               H             CH.sub.3                                                                              OH   allyl                                  3-HO.sub.2 C-benzyl                                                                       H             CH.sub.3                                                                              OH   allyl                                  3-H.sub.2 NCO-benzyl                                                                      H             CH.sub.3                                                                              OH   allyl                                  3-CH.sub.3 O-benzyl                                                                       H             CH.sub. 3                                                                             OH   allyl                                  3-HO-benzyl H             CH.sub.3                                                                              OH   allyl                                  3-Cl-benzyl H             CH.sub.3                                                                              OH   allyl                                  3-(CH.sub.3).sub.2 N-benzyl                                                               H             CH.sub.3                                                                              OH   allyl                                  4-pyridyl   H             CH.sub.3                                                                              OH   allyl                                  3-pyridyl   H             CH.sub.3                                                                              OH   allyl                                  2-pyridyl   H             CH.sub.3                                                                              OH   allyl                                  4-pyridylmethyl                                                                           H             CH.sub.3                                                                              OH   allyl                                  3-pyridylmethyl                                                                           H             CH.sub.3                                                                              OH   allyl                                  2-pyridylmethyl                                                                           H             CH.sub.3                                                                              OH   allyl                                  CH.sub.3    H             CH.sub.3                                                                              OH   ethyl                                  CH.sub.3 CH.sub.2                                                                         H             CH.sub.3                                                                              OH   ethyl                                  CH.sub.3 CH.sub.2 CH.sub.2                                                                H             CH.sub.3                                                                              OH   ethyl                                  (CH.sub.3).sub.2 CH                                                                       H             CH.sub.3                                                                              OH   ethyl                                  HO.sub.2 CCH.sub.2 CH.sub.2                                                               H             CH.sub.3                                                                              OH   ethyl                                  H.sub.2 NCOCH.sub.2 CH.sub.2                                                              H             CH.sub.3                                                                              OH   ethyl                                  HOCH.sub.2 CH.sub.2                                                                       H             CH.sub.3                                                                              OH   ethyl                                  HOCH.sub.2 CH.sub.2 CH.sub.2                                                              H             CH.sub.3                                                                              OH   ethyl                                  CH.sub.3    CH.sub.3      CH.sub.3                                                                              OH   ethyl                                  CH.sub.3 CH.sub.2                                                                         CH.sub.3 CH.sub.2                                                                           CH.sub.3                                                                              OH   ethyl                                  HOCH.sub.2 CH.sub.2                                                                       HOCH.sub.2 CH.sub.2                                                                         CH.sub.3                                                                              OH   ethyl                                  HOCH.sub.2 CH.sub.2 CH.sub.2                                                              HOCH.sub.2 CH.sub.2 CH.sub.2                                                                CH.sub.3                                                                              OH   ethyl                                  CH.sub.3    H             CH.sub.3                                                                              H    ethyl                                  CH.sub.3 CH.sub.2                                                                         H             CH.sub. 3                                                                             H    ethyl                                  CH.sub.3 CH.sub.2 CH.sub.2                                                                H             CH.sub.3                                                                              H    ethyl                                  (CH.sub.3).sub.2 CH                                                                       H             CH.sub.3                                                                              H    ethyl                                  HO.sub.2 CCH.sub.2 CH.sub.2                                                               H             CH.sub.3                                                                              H    ethyl                                  H.sub.2 NCOCH.sub.2 CH.sub.2                                                              H             CH.sub.3                                                                              H    ethyl                                  HOCH.sub.2 CH.sub.2                                                                       H             CH.sub.3                                                                              H    ethyl                                  HOCH.sub.2 CH.sub.2 CH.sub.2                                                              H             CH.sub.3                                                                              H    ethyl                                  CH.sub.3    CH.sub.3      CH.sub.3                                                                              H    ethyl                                  CH.sub.3 CH.sub.2                                                                         CH.sub.3 CH.sub.2                                                                           CH.sub.3                                                                              H    ethyl                                  CH.sub.3 CH.sub.2 CH.sub.2                                                                CH.sub.3 CH.sub.2 CH.sub.2                                                                  CH.sub.3                                                                              H    ethyl                                  HOCH.sub.2 CH.sub.2                                                                       HOCH.sub.2 CH.sub.2                                                                         CH.sub.3                                                                              H    ethyl                                  HOCH.sub.2 CH.sub.2 CH.sub.2                                                              HOCH.sub.2 CH.sub.2 CH.sub.2                                                                CH.sub.3                                                                              H    ethyl                                  CH.sub.3    H             H       OH   ethyl                                  CH.sub.3 CH.sub.2                                                                         H             H       OH   ethyl                                  CH.sub.3 CH.sub.2 CH.sub.2                                                                H             H       OH   ethyl                                  (CH.sub.3).sub.2 CH                                                                       H             H       OH   ethyl                                  HO.sub.2 CCH.sub.2 CH.sub.2                                                               H             H       OH   ethyl                                  H.sub.2 NCOCH.sub.2 CH.sub.2                                                              H             H       OH   ethyl                                  HOCH.sub.2 CH.sub.2                                                                       H             H       OH   ethyl                                  HOCH.sub.2 CH.sub.2 CH.sub.2                                                              H             H       OH   ethyl                                  CH.sub.3    CH.sub.3      H       OH   ethyl                                  CH.sub.3 CH.sub.2                                                                         CH.sub.3 CH.sub.2                                                                           H       OH   ethyl                                  CH.sub.3 CH.sub.2 CH.sub.2                                                                CH.sub.3 CH.sub.2 CH.sub.2                                                                  H       OH   ethyl                                  HOCH.sub.2 CH.sub.2                                                                       HOCH.sub.2 CH.sub.2                                                                         H       OH   ethyl                                  HOCH.sub.2 CH.sub.2 CH.sub.2                                                              HOCH.sub.2 CH.sub.2 CH.sub.2                                                                H       OH   ethyl                                  --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --                                                           CH.sub.3                                                                              H      ethyl                                    --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                   CH.sub.3                                                                              H      ethyl                                    --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --                                                           CH.sub.3                                                                              OH     ethyl                                    --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                   H       OH     ethyl                                    --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --                                                           H       OH     ethyl                                    --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                   H       OH     ethyl                                    --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --                                                           CH.sub.3                                                                              H      allyl                                    --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                   CH.sub.3                                                                              H      allyl                                    --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --                                                           CH.sub.3                                                                              OH     allyl                                    --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                   H       OH     allyl                                    --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --                                                           H       OH     allyl                                    --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                   H       OH     allyl.                                   ______________________________________                                    

Representative compounds of the present invention include the compoundsof formula XIV, XV, XVI and XVII: ##STR13## wherein R^(6a) is H or CH₃and R², R³, R⁵ and R⁶ are selected from the following groups ofsubstituents:

    ______________________________________                                        R.sup.6         R.sup.2  R.sup.3   R.sup.5                                    ______________________________________                                        H               CH.sub.3 OH        ethyl                                      CH.sub.3        CH.sub.3 OH        ethyl                                      CH.sub.3 CH.sub.2                                                                             CH.sub.3 OH        ethyl                                      CH.sub.2 ═CHCH.sub.2                                                                      CH.sub.3 OH        ethyl                                      CH.sub.3 CH.sub.2 CH.sub.2                                                                    CH.sub.3 OH        ethyl                                      (CH.sub.3).sub.2 CH                                                                           CH.sub.3 OH        ethyl                                      HO.sub.2 CCH.sub.2 CH.sub.2                                                                   CH.sub.3 OH        ethyl                                      H.sub.2 NCOCH.sub.2 CH.sub.2                                                                  CH.sub.3 OH        ethyl                                      HOCH.sub.2 CH.sub.2                                                                           CH.sub.3 OH        ethyl                                      HOCH.sub.2 CH.sub.2 CH.sub.2                                                                  CH.sub.3 OH        ethyl                                      (CH.sub.3).sub.2 CH.sub.2                                                                     CH.sub.3 OH        ethyl                                      phenyl          CH.sub.3 OH        ethyl                                      4-pyridyl       CH.sub.3 OH        ethyl                                      3-pyridyl       CH.sub.3 OH        ethyl                                      2-pyridyl       CH.sub.3 OH        ethyl                                      4-pyridylmethyl CH.sub.3 OH        ethyl                                      3-pyridylmethyl CH.sub.3 OH        ethyl                                      2-pyridylmethyl CH.sub.3 OH        ethyl                                      benzyl          CH.sub.3 OH        ethyl                                      4-HO.sub.2 C-benzyl                                                                           CH.sub.3 OH        ethyl                                      4-H.sub.2 NCO-benzyl                                                                          CH.sub.3 OH        ethyl                                      4-CH.sub.3 O-benzyl                                                                           CH.sub.3 OH        ethyl                                      4-HO-benzyl     CH.sub.3 OH        ethyl                                      4-Cl-benzyl     CH.sub.3 OH        ethyl                                      4-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 OH        ethyl                                      3-HO.sub.2 C-benzyl                                                                           CH.sub.3 OH        ethyl                                      3-H.sub.2 NCO-benzyl                                                                          CH.sub.3 OH        ethyl                                      3-CH.sub.3 -benzyl                                                                            CH.sub.3 OH        ethyl                                      3-HO-benzyl     CH.sub.3 OH        ethyl                                      3-Cl-benzyl     CH.sub.3 OH        ethyl                                      3-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 OH        ethyl                                      2-HO-benzyl     CH.sub.3 OH        ethyl                                      2-Cl-benzyl     CH.sub.3 OH        ethyl                                      2-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 OH        ethyl                                      CH.sub.3        CH.sub.3 H         ethyl                                      CH.sub.3 CH.sub.2                                                                             CH.sub.3 H         ethyl                                      CH.sub.2 ═CHCH.sub.2                                                                      CH.sub.3 H         ethyl                                      CH.sub.3 CH.sub.2 CH.sub.2                                                                    CH.sub.3 H         ethyl                                      (CH.sub.3).sub.2 CH                                                                           CH.sub.3 H         ethyl                                      HO.sub.2 CCH.sub.2 CH.sub.2                                                                   CH.sub.3 H         ethyl                                      H.sub.2 NCOCH.sub.2 CH.sub.2                                                                  CH.sub.3 H         ethyl                                      HOCH.sub.2 CH.sub.2                                                                           CH.sub.3 H         ethyl                                      HOCH.sub.2 CH.sub.2 CH.sub.2                                                                  CH.sub.3 H         ethyl                                      (CH.sub.3).sub.2 CH.sub.2                                                                     CH.sub.3 H         ethyl                                      phenyl          CH.sub.3 H         ethyl                                      4-pyridyl       CH.sub.3 H         ethyl                                      3-pyridyl       CH.sub.3 H         ethyl                                      2-pyridyl       CH.sub.3 H         ethyl                                      4-pyridylmethyl CH.sub.3 H         ethyl                                      3-pyridylmethyl CH.sub.3 H         ethyl                                      2-pyridylmethyl CH.sub.3 H         ethyl                                      benzyl          CH.sub.3 H         ethyl                                      4-HO.sub.2 C-benzyl                                                                           CH.sub.3 H         ethyl                                      4-H.sub.2 NCO-benzyl                                                                          CH.sub.3 H         ethyl                                      4-CH.sub.3 O-benzyl                                                                           CH.sub. 3                                                                              H         ethyl                                      4-HO-benzyl     CH.sub.3 H         ethyl                                      4-Cl-benzyl     CH.sub.3 H         ethyl                                      4-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 H         ethyl                                      3-HO.sub.2 C-benzyl                                                                           CH.sub.3 H         ethyl                                      3-H.sub.2 NCO-benzyl                                                                          CH.sub.3 H         ethyl                                      3-CH.sub.3 O-benzyl                                                                           CH.sub.3 H         ethyl                                      3-HO-benzyl     CH.sub.3 H         ethyl                                      3-Cl-benzyl     CH.sub.3 H         ethyl                                      3-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 H         ethyl                                      2-HO.sub.2 C-benzyl                                                                           CH.sub.3 H         ethyl                                      2-H.sub.2 NCO-benzyl                                                                          CH.sub.3 H         ethyl                                      2-CH.sub.3 O-benzyl                                                                           CH.sub.3 H         ethyl                                      2-HO-benzyl     CH.sub.3 H         ethyl                                      2-Cl-benzyl     CH.sub.3 H         ethyl                                      2-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 H         ethyl                                      CH.sub.3        CH.sub.3 OH        allyl                                      CH.sub.3 CH.sub.2                                                                             CH.sub.3 OH        allyl                                      CH.sub.2 ═CHCH.sub.2                                                                      CH.sub.3 OH        allyl                                      CH.sub.3 CH.sub.2 CH.sub.2                                                                    CH.sub.3 OH        allyl                                      (CH.sub.3).sub.2 CH                                                                           CH.sub.3 OH        allyl                                      HO.sub.2 CCH.sub.2 CH.sub.2                                                                   CH.sub.3 OH        allyl                                      H.sub.2 NCOCH.sub.2 CH.sub.2                                                                  CH.sub.3 OH        allyl                                      HOCH.sub.2 CH.sub.2                                                                           CH.sub.3 OH        allyl                                      HOCH.sub.2 CH.sub.2 CH.sub.2                                                                  CH.sub.3 OH        allyl                                      (CH.sub.3).sub.2 CH.sub.2                                                                     CH.sub.3 OH        allyl                                      phenyl          CH.sub.3 OH        allyl                                      4-pyridyl       CH.sub.3 OH        allyl                                      3-pyridyl       CH.sub.3 OH        allyl                                      2-pyridyl       CH.sub.3 OH        allyl                                      4-pyridylmethyl CH.sub.3 OH        allyl                                      3-pyridylmethyl CH.sub.3 OH        allyl                                      2-pyridylmethyl CH.sub.3 OH        allyl                                      benzyl          CH.sub.3 OH        allyl                                      4-HO.sub.2 C-benzyl                                                                           CH.sub.3 OH        allyl                                      4-H.sub.2 NCO-benzyl                                                                          CH.sub.3 OH        allyl                                      4-CH.sub.3 O-benzyl                                                                           CH.sub.3 OH        allyl                                      4-HO-benzyl     CH.sub.3 OH        allyl                                      4-Cl-benzyl     CH.sub.3 OH        allyl                                      4-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 OH        allyl                                      3-HO.sub.2 C-benzyl                                                                           CH.sub.3 OH        allyl                                      3-H.sub.2 NCO-benzyl                                                                          CH.sub.3 OH        allyl                                      3-CH.sub.3 O-benzyl                                                                           CH.sub.3 OH        allyl                                      3-HO-benzyl     CH.sub.3 OH        allyl                                      3-Cl-benzyl     CH.sub.3 OH        allyl                                      3-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 OH        allyl                                      2-HO.sub.2 C-benzyl                                                                           CH.sub.3 OH        allyl                                      2-H.sub.2 NCO-benzyl                                                                          CH.sub.3 OH        allyl                                      2-CH.sub.3 O-benzyl                                                                           CH.sub.3 OH        allyl                                      2-HO-benzyl     CH.sub.3 OH        allyl                                      2-Cl-benzyl     CH.sub.3 OH        allyl                                      2-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 OH        allyl.                                     ______________________________________                                    

Representative compounds of the present invention include the compoundsof Formula XVIII, XIX, XX and XXI: ##STR14## wherein R^(6a) is H or CH₃and R, R², R³ and R⁵ are selected from the following groups ofsubstituents:

    ______________________________________                                        R.sup.a         R.sup.2  R.sup.3   R.sup.5                                    ______________________________________                                        CH.sub.3        CH.sub.3 OH        ethyl                                      CH.sub.3 CH.sub.2                                                                             CH.sub.3 OH        ethyl                                      CH.sub.2 ═CHCH.sub.2                                                                      CH.sub.3 OH        ethyl                                      CH.sub.3 CH.sub.2 CH.sub.2                                                                    CH.sub.3 OH        ethyl                                      (CH.sub.3).sub.2 CH                                                                           CH.sub.3 OH        ethyl                                      HO.sub.2 CCH.sub.2 CH.sub.2                                                                   CH.sub.3 OH        ethyl                                      H.sub.2 NCOCH.sub.2 CH.sub.2                                                                  CH.sub.3 OH        ethyl                                      HOCH.sub.2 CH.sub.2                                                                           CH.sub.3 OH        ethyl                                      HOCH.sub.2 CH.sub.2 CH.sub.2                                                                  CH.sub.3 OH        ethyl                                      (CH.sub.3).sub.2 CH.sub.2                                                                     CH.sub.3 OH        ethyl                                      phenyl          CH.sub.3 OH        ethyl                                      4-pyridyl       CH.sub.3 OH        ethyl                                      3-pyridyl       CH.sub.3 OH        ethyl                                      2-pyridyl       CH.sub.3 OH        ethyl                                      4-pyridylmethyl CH.sub.3 OH        ethyl                                      3-pyridylmethyl CH.sub.3 OH        ethyl                                      2-pyridylmethyl CH.sub.3 OH        ethyl                                      benzyl          CH.sub.3 OH        ethyl                                      4-HO.sub.2 C-benzyl                                                                           CH.sub.3 OH        ethyl                                      4-H.sub.2 NCO-benzyl                                                                          CH.sub.3 OH        ethyl                                      4-CH.sub.3 O-benzyl                                                                           CH.sub.3 OH        ethyl                                      4-HO-benzyl     CH.sub.3 OH        ethyl                                      4-Cl-benzyl     CH.sub.3 OH        ethyl                                      4-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 OH        ethyl                                      3-HO.sub.2 C-benzyl                                                                           CH.sub.3 OH        ethyl                                      3-H.sub.2 NCO-benzyl                                                                          CH.sub. 3                                                                              OH        ethyl                                      3-CH.sub.3 O-benzyl                                                                           CH.sub.3 OH        ethyl                                      3-HO-benzyl     CH.sub.3 OH        ethyl                                      3-Cl-benzyl     CH.sub.3 OH        ethyl                                      3-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 OH        ethyl                                      2-HO.sub.2 C-benzyl                                                                           CH.sub.3 OH        ethyl                                      2-H.sub.2 NCO-benzyl                                                                          CH.sub.3 OH        ethyl                                      2-CH.sub.3 O-benzyl                                                                           CH.sub.3 OH        ethyl                                      2-HO-benzyl     CH.sub.3 OH        ethyl                                      2-Cl-benzyl     CH.sub.3 OH        ethyl                                      2-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 OH        ethyl                                      CH.sub.3        CH.sub.3 H         ethyl                                      CH.sub.3 CH.sub.2                                                                             CH.sub.3 H         ethyl                                      CH.sub.2 ═CHCH.sub.2                                                                      CH.sub.3 H         ethyl                                      CH.sub.3 CH.sub.2 CH.sub.2                                                                    CH.sub.3 H         ethyl                                      (CH.sub.3).sub.2 CH                                                                           CH.sub.3 H         ethyl                                      HO.sub.2 CCH.sub.2 CH.sub.2                                                                   CH.sub.3 H         ethyl                                      H.sub.2 NCOCH.sub.2 CH.sub.2                                                                  CH.sub.3 H         ethyl                                      HOCH.sub.2 CH.sub.2                                                                           CH.sub.3 H         ethyl                                      HOCH.sub.2 CH.sub.2 CH.sub.2                                                                  CH.sub.3 H         ethyl                                      (CH.sub.3).sub.2 CH.sub.2                                                                     CH.sub.3 H         ethyl                                      phenyl          CH.sub.3 H         ethyl                                      4-pyridyl       CH.sub.3 H         ethyl                                      3-pyridyl       CH.sub.3 H         ethyl                                      2-pyridyl       CH.sub.3 H         ethyl                                      4-pyridylmethyl CH.sub.3 H         ethyl                                      3-pyridylmethyl CH.sub.3 H         ethyl                                      2-pyridylmethyl CH.sub.3 H         ethyl                                      benzyl          CH.sub.3 H         ethyl                                      4-HO.sub.2 C-benzyl                                                                           CH.sub.3 H         ethyl                                      4-H.sub.2 NCO-benzyl                                                                          CH.sub.3 H         ethyl                                      4-CH.sub.3 O-benzyl                                                                           CH.sub.3 H         ethyl                                      4-HO-benzyl     CH.sub.3 H         ethyl                                      4-Cl-benzyl     CH.sub.3 H         ethyl                                      4-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 H         ethyl                                      3-HO.sub.2 C-benzyl                                                                           CH.sub.3 H         ethyl                                      3-H.sub.2 NCO-benzyl                                                                          CH.sub.3 H         ethyl                                      3-CH.sub.3 O-benzyl                                                                           CH.sub.3 H         ethyl                                      3-HO-benzyl     CH.sub.3 H         ethyl                                      3-Cl-benzyl     CH.sub.3 H         ethyl                                      3-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 H         ethyl                                      2-HO.sub.2 C-benzyl                                                                           CH.sub.3 H         ethyl                                      2-H.sub.2 NCO-benzyl                                                                          CH.sub.3 H         ethyl                                      2-CH.sub.3 O-benzyl                                                                           CH.sub.3 H         ethyl                                      2-HO-benzyl     CH.sub.3 H         ethyl                                      2-Cl-benzyl     CH.sub.3 H         ethyl                                      2-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 H         ethyl                                      CH.sub.3        CH.sub.3 OH        allyl                                      CH.sub.3 CH.sub.2                                                                             CH.sub.3 OH        allyl                                      CH.sub.2 ═CHCH.sub.2                                                                      CH.sub.3 OH        allyl                                      CH.sub.3 CH.sub.2 CH.sub.2                                                                    CH.sub.3 OH        allyl                                      (CH.sub.3).sub.2 CH                                                                           CH.sub.3 OH        allyl                                      HO.sub.2 CCH.sub.2 CH.sub.2                                                                   CH.sub.3 OH        allyl                                      H.sub.2 NCOCH.sub.2 CH.sub.2                                                                  CH.sub.3 OH        allyl                                      HOCH.sub.2 CH.sub.2                                                                           CH.sub.3 OH        allyl                                      HOCH.sub.2 CH.sub.2 CH.sub.2                                                                  CH.sub.3 OH        allyl                                      (CH.sub.3).sub.2 CH.sub.2                                                                     CH.sub.3 OH        allyl                                      phenyl          CH.sub.3 OH        allyl                                      4-pyridyl       CH.sub.3 OH        allyl                                      3-pyridyl       CH.sub.3 OH        allyl                                      2-pyridyl       CH.sub.3 OH        allyl                                      4-pyridylmethyl CH.sub.3 OH        allyl                                      3-pyridylmethyl CH.sub.3 OH        allyl                                      2-pyridylmethyl CH.sub.3 OH        allyl                                      benzyl          CH.sub.3 OH        allyl                                      4-HO.sub.2 C-benzyl                                                                           CH.sub.3 OH        allyl                                      4-H.sub.2 NCO-benzyl                                                                          CH.sub.3 OH        allyl                                      4-CH.sub.3 O-benzyl                                                                           CH.sub.3 OH        allyl                                      4-HO-benzyl     CH.sub.3 OH        allyl                                      4-Cl-benzyl     CH.sub.3 OH        allyl                                      4-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 OH        allyl                                      3-HO.sub.2 C-benzyl                                                                           CH.sub.3 OH        allyl                                      3-H.sub.2 NCO-benzyl                                                                          CH.sub.3 OH        allyl                                      3-CH.sub.3 O-benzyl                                                                           CH.sub.3 OH        allyl                                      3-HO-benzyl     CH.sub.3 OH        allyl                                      3-Cl-benzyl     CH.sub.3 OH        allyl                                      3-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 OH        allyl                                      2-HO.sub.2 C-benzyl                                                                           CH.sub.3 OH        allyl                                      2-H.sub.2 NCO-benzyl                                                                          CH.sub.3 OH        allyl                                      2-CH.sub.3 O-benzyl                                                                           CH.sub.3 OH        allyl                                      2-HO-benzyl     CH.sub.3 OH        allyl                                      2-Cl-benzyl     CH.sub.3 OH        allyl                                      2-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3 OH        allyl.                                     ______________________________________                                    

Representative compounds of the present invention include the compoundsof Formula XVIII: ##STR15## wherein X, R², R³ and R⁵ are selected fromthe following groups of substituents:

    ______________________________________                                        X                      R.sup.2                                                                              R.sup.3 R.sup.5                                 ______________________________________                                        1-imidazolylmethyl     CH.sub.3                                                                             OH      ethyl                                   2-imidazolylmethyl     CH.sub.3                                                                             OH      ethyl                                   3-thiazolylmethyl      CH.sub.3                                                                             OH      ethyl                                   2-thiazolylmethyl      CH.sub.3                                                                             OH      ethyl                                   2-oxazolylmethyl       CH.sub.3                                                                             OH      ethyl                                   5-tetrazolylmethyl     CH.sub.3                                                                             OH      ethyl                                   4-pyridylmethyl        CH.sub.3                                                                             OH      ethyl                                   3-pyridylmethyl        CH.sub.3                                                                             OH      ethyl                                   2-pyridylmethyl        CH.sub.3                                                                             OH      ethyl                                   benzyl                 CH.sub.3                                                                             OH      ethyl                                   4-HO.sub.2 C-benzyl    CH.sub.3                                                                             OH      ethyl                                   4-H.sub.2 NCO-benzyl   CH.sub.3                                                                             OH      ethyl                                   4-CH.sub.3 O-benzyl    CH.sub.3                                                                             OH      ethyl                                   4-HO-benzyl            CH.sub.3                                                                             OH      ethyl                                   4-R.sup.11 O-benzyl    CH.sub.3                                                                             OH      ethyl                                   4-Cl-benzyl            CH.sub.3                                                                             OH      ethyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             OH      ethyl                                   3-HO.sub.2 C-benzyl    CH.sub.3                                                                             OH      ethyl                                   3-H.sub.2 NCO-benzyl   CH.sub.3                                                                             OH      ethyl                                   3-CH.sub.3 O-benzyl    CH.sub.3                                                                             OH      ethyl                                   3-HO-benzyl            CH.sub.3                                                                             OH      ethyl                                   3-R.sup.11 O-benzyl    CH.sub.3                                                                             OH      ethyl                                   3-Cl-benzyl            CH.sub.3                                                                             OH      ethyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             OH      ethyl                                   2-HO.sub.2 C-benzyl    CH.sub.3                                                                             OH      ethyl                                   2-H.sub.2 NCO-benzyl   CH.sub.3                                                                             OH      ethyl                                   2-CH.sub.3 O-benzyl    CH.sub.3                                                                             OH      ethyl                                   2-HO-benzyl            CH.sub.3                                                                             OH      ethyl                                   2-R.sup.11 O-benzyl    CH.sub.3                                                                             OH      ethyl                                   2-Cl-benzyl            CH.sub.3                                                                             OH      ethyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             OH      ethyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             OH      ethyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             OH      ethyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             OH      ethyl                                   3-phenylimidazol-2-ylmethyl                                                                          CH.sub.3                                                                             OH      ethyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(4-H.sub.2 NCO-phenyl-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      ethyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      ethyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl-imidazol-2-ylmethyl                                                   CH.sub.3                                                                             OH      ethyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      ethyl                                   3-(3-R.sup.11 O-phenyl-imidazol-2-ylmethyl                                                           CH.sub.3                                                                             OH      ethyl                                   3-(3-Cl-phenyl-imidazol-2-ylmethyl                                                                   CH.sub.3                                                                             OH      ethyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             OH      ethyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             OH      ethyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      ethyl                                   3-(2-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(2-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      ethyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl-imidazol-2-ylmethyl                                                   CH.sub.3                                                                             OH      ethyl                                   1-imidazolylmethyl     CH.sub.3                                                                             H       ethyl                                   2-imidazolylmethyl     CH.sub.3                                                                             H       ethyl                                   3-thiazolylmethyl      CH.sub.3                                                                             H       ethyl                                   2-thiazolylmethyl      CH.sub.3                                                                             H       ethyl                                   2-oxazolylmethyl       CH.sub.3                                                                             H       ethyl                                   5-tetrazolylmethyl     CH.sub.3                                                                             H       ethyl                                   4-pyridylmethyl        CH.sub.3                                                                             H       ethyl                                   3-pyridylmethyl        CH.sub.3                                                                             H       ethyl                                   2-pyridylmethyl        CH.sub.3                                                                             H       ethyl                                   benzyl                 CH.sub.3                                                                             H       ethyl                                   4-HO.sub.2 C-benzyl    CH.sub.3                                                                             H       ethyl                                   4-H.sub.2 NCO-benzyl   CH.sub.3                                                                             H       ethyl                                   4-CH.sub.3 O-benzyl    CH.sub.3                                                                             H       ethyl                                   4-HO-benzyl            CH.sub.3                                                                             H       ethyl                                   4-R.sup.11 O-benzyl    CH.sub.3                                                                             H       ethyl                                   4-Cl-benzyl            CH.sub.3                                                                             H       ethyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             H       ethyl                                   3-HO.sub.2 C-benzyl    CH.sub.3                                                                             H       ethyl                                   3-H.sub.2 NCO-benzyl   CH.sub.3                                                                             H       ethyl                                   3-CH.sub.3 O-benzyl    CH.sub.3                                                                             H       ethyl                                   3-HO-benzyl            CH.sub.3                                                                             H       ethyl                                   3-R.sup.11 O-benzyl    CH.sub.3                                                                             H       ethyl                                   3-Cl-benzyl            CH.sub.3                                                                             H       ethyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             H       ethyl                                   2-HO.sub.2 C-benzyl    CH.sub.3                                                                             H       ethyl                                   2-H.sub.2 NCO-benzyl   CH.sub.3                                                                             H       ethyl                                   2-CH.sub.3 O-benzyl    CH.sub.3                                                                             H       ethyl                                   2-HO-benzyl            CH.sub.3                                                                             H       ethyl                                   2-R.sup.11 O-benzyl    CH.sub.3                                                                             H       ethyl                                   2-Cl-benzyl            CH.sub.3                                                                             H       ethyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             H       ethyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             H       ethyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             H       ethyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             H       ethyl                                   3-phenylimidazol-2-ylmethyl                                                                          CH.sub.3                                                                             H       ethyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       ethyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             H       ethyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       ethyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       ethyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       ethyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       ethyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             H       ethyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       ethyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             H       ethyl                                   3-(3-CH.sub.3 O-phenyl-imidazol-2-ylmethyl                                                           CH.sub.3                                                                             H       ethyl                                   3-(3-HO-phenyl-imidazol-2-ylmethyl                                                                   CH.sub.3                                                                             H       ethyl                                   3-(3-R.sup.11 O-phenyl-imidazol-2-ylmethyl                                                           CH.sub.3                                                                             H       ethyl                                   3-(3-Cl-phenyl-imidazol-2-ylmethyl                                                                   CH.sub.3                                                                             H       ethyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl-imidazol-2-ylmethyl                                                   CH.sub.3                                                                             H       ethyl                                   3-(2-HO.sub.2 C-phenyl-imidazol-2-ylmethyl                                                           CH.sub.3                                                                             H       ethyl                                   3-(2-H.sub.2 NCO-phenyl-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       ethyl                                   3-(2-CH.sub.3 O-phenyl-imidazol-2-ylmethyl                                                           CH.sub.3                                                                             H       ethyl                                   3-(2-HO-phenyl-imidazol-2-ylmethyl                                                                   CH.sub.3                                                                             H       ethyl                                   3-(2-R.sup.11 O-phenyl-imidazol-2-ylmethyl                                                           CH.sub.3                                                                             H       ethyl                                   3-(2-Cl-phenyl-imidazol-2-ylmethyl                                                                   CH.sub.3                                                                             H       ethyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl-imidazol-2-ylmethyl                                                   CH.sub.3                                                                             H       ethyl                                   1-imidazolylmethyl     H      OH      ethyl                                   2-imidazolylmethyl     H      OH      ethyl                                   3-thiazolylmethyl      H      OH      ethyl                                   2-thiazolylmethyl      H      OH      ethyl                                   2-oxazolylmethyl       H      OH      ethyl                                   5-tetrazolylmethyl     H      OH      ethyl                                   4-pyridylmethyl        H      OH      ethyl                                   3-pyridylmethyl        H      OH      ethyl                                   2-pyridylmethyl        H      OH      ethyl                                   benzyl                 H      OH      ethyl                                   4-HO.sub.2 C-benzyl    H      OH      ethyl                                   4-H.sub.2 NCO-benzyl   H      OH      ethyl                                   4-CH.sub.3 O-benzyl    H      OH      ethyl                                   4-HO-benzyl            H      OH      ethyl                                   4-R.sup.11 O-benzyl    H      OH      ethyl                                   4-Cl-benzyl            H      OH      ethyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          H      OH      ethyl                                   3-HO.sub.2 C-benzyl    H      OH      ethyl                                   3-H.sub.2 NCO-benzyl   H      OH      ethyl                                   3-CH.sub.3 O-benzyl    H      OH      ethyl                                   3-HO-benzyl            H      OH      ethyl                                   3-R.sup.11 O-benzyl    H      OH      ethyl                                   3-Cl-benzyl            H      OH      ethyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          H      OH      ethyl                                   2-HO.sub.2 C-benzyl    H      OH      ethyl                                   2-H.sub.2 NCO-benzyl   H      OH      ethyl                                   2-CH.sub.3 O-benzyl    H      OH      ethyl                                   2-HO-benzyl            H      OH      ethyl                                   2-R.sup.11 O-benzyl    H      OH      ethyl                                   2-Cl-benzyl            H      OH      ethyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          H      OH      ethyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    H      OH      ethyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    H      OH      ethyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    H      OH      ethyl                                   3-phenylimidazol-2-ylmethyl                                                                          H      OH      ethyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      OH      ethyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      ethyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      ethyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      OH      ethyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      OH      ethyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      ethyl                                   3-(3-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(3-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      ethyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      OH      ethyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      OH      ethyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      ethyl                                   3-(2-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(2-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      ethyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      OH      ethyl                                   1-imidazolylmethyl     H      H       ethyl                                   2-imidazolylmethyl     H      H       ethyl                                   3-thiazolylmethyl      H      H       ethyl                                   2-thiazolylmethyl      H      H       ethyl                                   2-oxazolylmethyl       H      H       ethyl                                   5-tetrazolylmethyl     H      H       ethyl                                   4-pyridylmethyl        H      H       ethyl                                   3-pyridylmethyl        H      H       ethyl                                   2-pyridylmethyl        H      H       ethyl                                   benzyl                 H      H       ethyl                                   4-HO.sub.2 C-benzyl    H      H       ethyl                                   4-H.sub.2 NCO-benzyl   H      H       ethyl                                   4-CH.sub.3 O-benzyl    H      H       ethyl                                   4-HO-benzyl            H      H       ethyl                                   4-R.sup.11 O-benzyl    H      H       ethyl                                   4-Cl-benzyl            H      H       ethyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          H      H       ethyl                                   3-HO.sub.2 C-benzyl    H      H       ethyl                                   3-H.sub.2 NCO-benzyl   H      H       ethyl                                   3-CH.sub.3 O-benzyl    H      H       ethyl                                   3-HO-benzyl            H      H       ethyl                                   3-R.sup.11 O-benzyl    H      H       ethyl                                   3-Cl-benzyl            H      H       ethyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          H      H       ethyl                                   2-HO.sub.2 C-benzyl    H      H       ethyl                                   2-H.sub.2 NCO-benzyl   H      H       ethyl                                   2-CH.sub.3 O-benzyl    H      H       ethyl                                   2-HO-benzyl            H      H       ethyl                                   2-R.sup.11 O-benzyl    H      H       ethyl                                   2-Cl-benzyl            H      H       ethyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          H      H       ethyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    H      H       ethyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    H      H       ethyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    H      H       ethyl                                   3-phenylimidazol-2-ylmethyl                                                                          H      H       ethyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      H       ethyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      H       ethyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      H       ethyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      H       ethyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      H       ethyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      H       ethyl                                   3-(3-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(3-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      H       ethyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      H       ethyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      H       ethyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      H       ethyl                                   3-(2-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(2-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      H       ethyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      H       ethyl                                   1-imidazolylmethyl     CH.sub.3                                                                             OH      allyl                                   2-imidazolylmethyl     CH.sub.3                                                                             OH      allyl                                   3-thiazolylmethyl      CH.sub.3                                                                             OH      allyl                                   2-thiazolylmethyl      CH.sub.3                                                                             OH      allyl                                   2-oxazolylmethyl       CH.sub.3                                                                             OH      allyl                                   5-tetrazolylmethyl     CH.sub.3                                                                             OH      allyl                                   4-pyridylmethyl        CH.sub.3                                                                             OH      allyl                                   3-pyridylmethyl        CH.sub.3                                                                             OH      allyl                                   2-pyridylmethyl        CH.sub.3                                                                             OH      allyl                                   benzyl                 CH.sub.3                                                                             OH      allyl                                   4-HO.sub.2 C-benzyl    CH.sub.3                                                                             OH      allyl                                   4-H.sub.2 NCO-benzyl   CH.sub.3                                                                             OH      allyl                                   4-CH.sub.3 O-benzyl    CH.sub.3                                                                             OH      allyl                                   4-HO-benzyl            CH.sub.3                                                                             OH      allyl                                   4-R.sup.11 O-benzyl    CH.sub.3                                                                             OH      allyl                                   4-Cl-benzyl            CH.sub.3                                                                             OH      allyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             OH      allyl                                   3-HO.sub.2 C-benzyl    CH.sub.3                                                                             OH      allyl                                   3-H.sub.2 NCO-benzyl   CH.sub.3                                                                             OH      allyl                                   3-CH.sub.3 O-benzyl    CH.sub.3                                                                             OH      allyl                                   3-HO-benzyl            CH.sub.3                                                                             OH      allyl                                   3-R.sup.11 O-benzyl    CH.sub.3                                                                             OH      allyl                                   3-Cl-benzyl            CH.sub.3                                                                             OH      allyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             OH      allyl                                   2-HO.sub.2 C-benzyl    CH.sub.3                                                                             OH      allyl                                   2-H.sub.2 NCO-benzyl   CH.sub.3                                                                             OH      allyl                                   2-CH.sub.3 O-benzyl    CH.sub.3                                                                             OH      allyl                                   2-HO-benzyl            CH.sub.3                                                                             OH      allyl                                   2-R.sup.11 O-benzyl    CH.sub.3                                                                             OH      allyl                                   2-Cl-benzyl            CH.sub.3                                                                             OH      allyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             OH      allyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             OH      allyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             OH      allyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             OH      allyl                                   3-phenylimidazol-2-ylmethyl                                                                          CH.sub.3                                                                             OH      allyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             OH      allyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      allyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      allyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             OH      allyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             OH      allyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      allyl                                   3-(3-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(3-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      allyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             OH      allyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             OH      allyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      allyl                                   3-(2-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(2-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      allyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             OH      allyl                                   1-imidazolylmethyl     CH.sub.3                                                                             H       allyl                                   2-imidazolylmethyl     CH.sub.3                                                                             H       allyl                                   3-thiazolylmethyl      CH.sub.3                                                                             H       allyl                                   2-thiazolylmethyl      CH.sub.3                                                                             H       allyl                                   2-oxazolylmethyl       CH.sub.3                                                                             H       allyl                                   5-tetrazolylmethyl     CH.sub.3                                                                             H       allyl                                   4-pyridylmethyl        CH.sub.3                                                                             H       allyl                                   3-pyridylmethyl        CH.sub.3                                                                             H       allyl                                   2-pyridylmethyl        CH.sub.3                                                                             H       allyl                                   benzyl                 CH.sub.3                                                                             H       allyl                                   4-HO.sub.2 C-benzyl    CH.sub.3                                                                             H       allyl                                   4-H.sub.2 NCO-benzyl   CH.sub.3                                                                             H       allyl                                   4-CH.sub.3 O-benzyl    CH.sub.3                                                                             H       allyl                                   4-HO-benzyl            CH.sub.3                                                                             H       allyl                                   4-R.sup.11 O-benzyl    CH.sub.3                                                                             H       allyl                                   4-Cl-benzyl            CH.sub.3                                                                             H       allyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             H       allyl                                   3-HO.sub.2 C-benzyl    CH.sub.3                                                                             H       allyl                                   3-H.sub.2 NCO-benzyl   CH.sub.3                                                                             H       allyl                                   3-CH.sub.3 O-benzyl    CH.sub.3                                                                             H       allyl                                   3-HO-benzyl            CH.sub.3                                                                             H       allyl                                   3-R.sup.11 O-benzyl    CH.sub.3                                                                             H       allyl                                   3-Cl-benzyl            CH.sub.3                                                                             H       allyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             H       allyl                                   2-HO.sub.2 C-benzyl    CH.sub.3                                                                             H       allyl                                   2-H.sub.2 NCO-benzyl   CH.sub.3                                                                             H       allyl                                   2-CH.sub.3 O-benzyl    CH.sub.3                                                                             H       allyl                                   2-HO-benzyl            CH.sub.3                                                                             H       allyl                                   2-R.sup.11 O-benzyl    CH.sub.3                                                                             H       allyl                                   2-Cl-benzyl            CH.sub.3                                                                             H       allyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             H       allyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             H       allyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             H       allyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             H       allyl                                   3-phenylimidazol-2-ylmethyl                                                                          CH.sub.3                                                                             H       allyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             H       allyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       allyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       allyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             H       allyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             H       allyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       allyl                                   3-(3-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(3-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       allyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             H       allyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             H       allyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       allyl                                   3-(2-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(2-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       allyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             H       allyl                                   1-imidazolylmethyl     H      OH      allyl                                   2-imidazolymethyl      H      OH      allyl                                   3-thiazolylmethyl      H      OH      allyl                                   2-thiazolylmethyl      H      OH      allyl                                   2-oxazolylmethyl       H      OH      allyl                                   5-tetrazolylmethyl     H      OH      allyl                                   4-pyridylmethyl        H      OH      allyl                                   3-pyridylmethyl        H      OH      allyl                                   2-pyridylmethyl        H      OH      allyl                                   benzyl                 H      OH      allyl                                   4-HO.sub.2 C-benzyl    H      OH      allyl                                   4-H.sub.2 NCO-benzyl   H      OH      allyl                                   4-CH.sub.3 O-benzyl    H      OH      allyl                                   4-HO-benzyl            H      OH      allyl                                   4-R.sup.11 O-benzyl    H      OH      allyl                                   4-Cl-benzyl            H      OH      allyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          H      OH      allyl                                   3-HO.sub.2 C-benzyl    H      OH      allyl                                   3-H.sub.2 NCO-benzyl   H      OH      allyl                                   3-CH.sub.3 O-benzyl    H      OH      allyl                                   3-HO-benzyl            H      OH      allyl                                   3-R.sup.11 O-benzyl    H      OH      allyl                                   3-Cl-benzyl            H      OH      allyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          H      OH      allyl                                   3-HO.sub.2 C-benzyl    H      OH      allyl                                   2-H.sub.2 NCO-benzyl   H      OH      allyl                                   2-CH.sub.3 O-benzyl    H      OH      allyl                                   2-HO-benzyl            H      OH      allyl                                   2-R.sup.11 O-benzyl    H      OH      allyl                                   2-Cl-benzyl            H      OH      allyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          H      OH      allyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    H      OH      allyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    H      OH      allyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    H      OH      allyl                                   3-phenylimidazol-2-ylmethyl                                                                          H      OH      allyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      OH      allyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      allyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      allyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      OH      allyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      OH      allyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      allyl                                   3-(3-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(3-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      allyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      OH      allyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      OH      allyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      allyl                                   3-(2-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(2-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      allyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      OH      allyl                                   1-imidazolylmethyl     H      H       allyl                                   2-imidazolylmethyl     H      H       allyl                                   3-thiazolylmethyl      H      H       allyl                                   2-thiazolylmethyl      H      H       allyl                                   2-oxazoylmethyl        H      H       allyl                                   5-tetrazolylmethyl     H      H       allyl                                   4-pyridylmethyl        H      H       allyl                                   3-pyridylmethyl        H      H       allyl                                   2-pyridylmethyl        H      H       allyl                                   benzyl                 H      H       allyl                                   4-HO.sub.2 C-benzyl    H      H       allyl                                   4-H.sub.2 NCO-benzyl   H      H       allyl                                   4-CH.sub.3 O-benzyl    H      H       allyl                                   4-HO-benzyl            H      H       allyl                                   4-R.sup.11 O-benzyl    H      H       allyl                                   4-Cl-benzyl            H      H       allyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          H      H       allyl                                   3-HO.sub.2 C-benzyl    H      H       allyl                                   3-H.sub.2 NCO-benzyl   H      H       allyl                                   3-CH.sub.3 O-benzyl    H      H       allyl                                   3-HO-benzyl            H      H       allyl                                   3-R.sup.11 O-benzyl    H      H       allyl                                   3-Cl-benzyl            H      H       allyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          H      H       allyl                                   2-HO.sub.2 C-benzyl    H      H       allyl                                   2-H.sub.2 NCO-benzyl   H      H       allyl                                   2-CH.sub.3 O-benzyl    H      H       allyl                                   2-HO-benzyl            H      H       allyl                                   2-R.sup.11 O-benzyl    H      H       allyl                                   2-Cl-benzyl            H      H       allyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          H      H       allyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    H      H       allyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    H      H       allyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    H      H       allyl                                   3-phenylimidazol-2-ylmethyl                                                                          H      H       allyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      H       allyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      H       allyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      H       allyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      H       allyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      H       allyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      H       allyl                                   3-(3-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(3-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      H       allyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      H       allyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      H       allyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      H       allyl                                   3-(2-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(2-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      H       allyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      H       allyl.                                  ______________________________________                                    

B. Preparation of Compounds Within the Scope of the Present Invention

The starting materials for the preparation of the compounds of thisinvention are represented by Formula II: ##STR16## wherein: E ishydrogen or methyl;

W is O or (H, OH);

R³ is hydrogen, hydroxy, or C₁₋₆ alkoxy;

R⁴ is hydrogen, or R³ and R⁴ taken together form a double bond;

R⁵ is methyl, ethyl, propyl or allyl; and

n is 1 or 2.

The production and characterization of compounds of Formula II is wellknown in the literature (see U.S. Pat. No. 4,894,366 issued Jan. 16,1990; U.S. Pat. No. 4,929,611 issued May 29, 1990; U.S. Pat. No.3,244,592 issued Apr. 15, 1966; EPO Publication No. 0,323,042,; EPOPublication No. 0,356,399; PBJ Disclosure 63-17884; J. Am. Chem. Soc.,1987, 109, 5031; J. Antibiotics, 1987, 40, 1249, J. Antibiotics, 1988,41(11), 1592; and J. Antibiotics, 1992, 45(1), 118). Both biologicalfermentation and synthetic processes may be found. A synthetic route tocompounds of Formula II can involve modifications of a route describedin J. Am. Chem. Soc., 1989, 111, 1157.

Biological fermentation followed by synthetic modification is presentlyfavored in the art as the method to produce compounds of Formula II.Organisms belonging to the genus Streptomyces such as Streptomycestsukubaensis, No. 9993 and Streptomyces hygroscopicus, var. ascomycetis,No. 14891 placed in an aqueous nutrient medium will produce desiredcompounds in isolable amounts. The nutrient medium contains sources ofassimilable carbon and nitrogen, preferably under aerobic conditions.Produced in fermentation are four compounds of Formula II, (A) where Eis methyl, W is O, R³ is hydroxyl, R⁴ is hydrogen, R⁵ is allyl and n is2; (B) where E is methyl, W is O, R³ is hydroxyl, R⁴ is hydrogen, R⁵ isethyl and n is 2; (C) where E is methyl, W is O, R³ is hydroxyl, R⁴ ishydrogen, R⁵ is methyl and n is 2; and (D) where E is methyl W is O, R³is hydroxyl, R⁴ is hydrogen, R⁵ is allyl and n is 1.

A lyophilized sample of the isolated Streptomyces tsukubaensis, No. 9993was deposited with the Fermentation Research Institute, Agency ofIndustrial Science and Technology (No. 1-3, Higashi 1-chome, YatabemachiTsukuba-gun, Ibaraki Prefecture, Japan) under the deposit number of FERMP-7886 (deposit date: Oct. 5th, 1984), and then converted to BudapestTreaty route of the same depository on Oct. 19, 1985 under the newdeposit number of FERM BP-927.

Using the four compounds produced in fermentation above, the remainingcompounds of Formula II may be easily produced. The allyl of R⁵ may beconveniently reduced to propyl by well known methods, for example asdescribed in U.S. Pat. No. 4,894,366. The hydroxy of R³ may be protectedby well known methods, for example as disclosed in EPO Publication No.0,323,042. Likewise, the hydroxyl at C-4" may also be protected. Inaddition, the hydroxy of R³ may be reduced to a hydrogen or eliminatedto form a double bond with R⁴ (by methods disclosed in U.S. Pat. No.4,894,366, EPO Publication No. 0,323,042 or EPO Publication No.0,413,532). The carbonyl of W may be reduced to the alcohol by methodsdisclosed in EPO Publication No. 0,323,042 or by methods disclosed inEPO Publication No. 0,445,975.

The methyl of E as produced may be replaced with hydrogen ordemethylated and subsequently protected as desired, if necessary. Thisdemethylation of compounds wherein E is methyl may be carried out in afermentation reaction using the compounds of Formula II as a feedstock.For instance, compound A named under Formula II above may bedemethylated at E above by using the microorganism Actinomycetales ATCCNo. 53771 (described in U.S. Pat. No. 4,981,792) or by using themicroorganism Streptomyces tsukubaensis, No. 9993 (described in EPOPublication No. 0,353,678). Similarly, compound B named under Formula IIabove may be demethylated at E above using the microorganismActinoplanacete sp. ATCC No. 53771 (described in EPO Publication No.0,349,061). In addition the compound of Formula II wherein E is H, W isO, R³ is hydroxy, R⁴ is hydrogen, R⁵ is ethyl and n is 2 may be produceddirectly by fermentation using the mutant microorganism Streptomyceshygroscopicus sup. ascomyceticus, No. 53855 (being a blocked mutant ofStreptomyces hygroscopicus sup. ascomyceticus, No. 14891) (as describedin EPO Publication No. 0,388,152). Similarly, the compound of Formula IIwherein E is hydrogen, W is O, R³ is hydroxy, R⁴ is hydrogen, R⁵ ismethyl and n is 2 may be produced directly by fermentation using themutant microorganism Streptomyces hygroscopicus sup. ascomyceticus, No.53855 (being a blocked mutant of Streptomyces hygroscopicus sup.ascomyceticus, No. 14891) (EPO Publication No. 0,388,153). The hydroxyof C-3" may be protected by methods similar to those known for theprotection of the hydroxyl groups of R³ and/or C-4", for example asdisclosed in U.S. Pat. No. 4,894,366.

Suitable protecting groups for hydroxyl include those groups well knownin the art such as: methylthiomethyl, ethylthiomethyl; trisubstitutedsilyl such as trimethylsilyl, triethylsilyl, tributylsilyl,tri-i-propylsilyl, t-butyldimethylsilyl, tri-t-butylsilyl,methyl-diphenylsilyl, ethyldiphenylsilyl, t-butyldiphenylsilyl, and thelike; acyl such as acetyl, pivaloyl benzoyl, 4-methoxybenzoyl,4-nitrobenzoyl and aliphatic acyl substituted with aromatic group, whichare derived from carboxylic acids; and the like.

Compounds A, B, C and D of Formula II, organisms to produce the same,conditions of fermentation, separation techniques, and chemicalmodification of the products are fully described in U.S. Pat. No.4,894,366, dated Jan. 16, 1990, U.S. Pat. No. 4,929,611, issued May 29,1990 and U.S. Pat. No. 5,110,811, issued May 5, 1992.

The novel processes for preparing the novel compounds of the presentinvention are illustrated as follows, wherein R¹, R², R³, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, E, W and n are as defined above unless otherwiseindicated. It will be readily apparent to one of ordinary skill in theart reviewing the synthetic route depicted below that other compoundswithin Formula I can be synthesized by substitution of appropriatereactants and agents in the synthesis shown below. ##STR17##

Reaction Scheme A

As shown in Reaction Scheme A, a solution of a 4"-hydroxy-3"-methoxymacrolide 1 in an inert organic solvent such as methylene chloride,benzene, toluene, chloroform, or the like or mixtures thereof is treatedwith a triheteroarylbismuth diacetate reagent (wherein R¹ is heteroaryl)(prepared immediately prior to use by the addition of acetic acid to asuspension of a triheteroarylbismuth carbonate in an inert organicsolvent such as methylene chloride, choroform or the like or mixturethereof) in the presence of a catalytic amount of copper(II) acetate ata temperature of 20°-50° C., preferably room temperature, for a periodof one hour to seven days, preferably one day, to give the4"-O-heteroaryl-3"-methoxy macrolide 2. Alternatively, thetriheteroarylbismuth(V) reagent can be prepared by treatment of atriheteroarylbismuthine with a suitable oxidant such as peracetic acid,benzoyl peroxide, hydrogen peroxide, iodobenzene diacetate,bis(trifluoroacetoxy) iodobenzene and the like in an inert solvent suchas methylene chloride, chloroform, benzene, toluene and the like. Thetriheteroarylbismuth(V) reagent can be used without purification or canbe purified by silica gel chromatography. Triheteroarylbismuthines maybe prepared by the reaction of an appropriate heteroaryl Grignardreagent or lithiated heteroaryl species with bismuth trichloride in aninert organic solvent such as tetrahydrofuran, diethyl ether, toluene,or 1,4-dioxane, or mixtures thereof, at or near room temperature for aperiod of 1 to 48 hours. General procedures for the preparation and useof triaryl bismuth reagents may be found in Barton, D.H.E., et al., J.Chem. Soc. Chem. Commun., 1986, 65 and references cited therein.

Reaction Scheme B:

Similarly, as shown in Reaction Scheme B, a solution of the3",4"-dihydroxy macrolide 3 treated with a triheteroarylbismuthdiacetate reagent as described in Reaction Scheme A, to give a mixtureof the 3"-hydroxy-4"-O-heteroaryl macrolide 4a, the3"-O-heteroaryl-4"-hydroxy macrolide 4b, and the 3",4"-di-O-heteroarylmacrolide 4c. At this stage, a solution of 3"-hydroxy-4"-O-heteroarylmacrolide 4a, or 3"-O-heteroaryl-4"-hydroxy macrolide 4B can be treatedwith a triarylbismuth diacetate reagent (prepared immediately prior touse by procedures analogous to those disclosed above), to give3"-O-aryl-4"-O-heteroaryl macrolide 5a, or 3"-O-heteroaryl-4"-O-arylmacrolide 5a, respectively.

Reaction Scheme C:

As shown in Reaction Scheme C the 14-hydroxy group of a macrolide 5a or5b (wherein R¹, R², R⁵, R¹⁰, W and n are as defined above) may beeliminated by treatment with p-toluenesulfonic acid, benzenesulfonicacid or methanesulfonic acid in an inert organic solvent such asbenzene, or toluene at from 40° C. to 60° C., for about 0.5 to 6 hours,or a sufficient period of time to eliminate the 14-hydroxy group.Neutralization with an aqueous solution of a weak base such as aqueoussaturated sodium bicarbonate gives the 14,15-dehydro macrolides 6a or6b. The 14-hydroxy group may also be eliminated by activation followedby basic elimination, as described in U.S. Pat. No. 4,894,366.

By changing the sequence of synthetic steps, all possible variations ofsubstitution can be achieved.

Reaction Scheme D:

As shown in Reaction Scheme D, a solution of the 4"-hydroxy 3"-methoxymacrolide 1 in an inert organic solvent such as methylene chloride,chloroform, pentane, hexane, cyclohexane, heptane or mixtures thereof istreated with a heteroarylalkyl, heteroarylalkenyl or heteroarylalkynyltrichloroacetimidate reagent (prepared by the reaction of an appropriatesodium alkoxide with trichloroacetonitrile, such as described by Wessel,H. P., Iversen, T., Bundle, D. R., J. Chem. Soc., Perkin Trans. I, 1985,2247) in the presence of a mild acid catalyst such astrifluoro-methanesulfonic acid, p-toluenesulfonic acid, methanesulfonicacid, or mixtures thereof at a temperature of 20°-50° C. for a period offrom one hour to seven days to give the 4"-O-heteroarylalkyl-,4"-O-heteroarylalkenyl- or 4"-O-heteroarylalkynyl-3"-methoxy macrolide2a.

Reaction Scheme E:

Similarly, as shown in Reaction Scheme E, a solution of the 3",4"-dihydroxy macrolide 3 in an inert organic solvent such as methylenechloride, chloroform, pentane, hexane, cyclohexane, heptane or the likeor mixtures thereof is treated with a heteroarylalkyl, heteroarylalkenylor heteroarylalkynyl trichloroacetimidate (prepared as described inReaction Scheme D) at a temperature of 20°-50° C., preferably 40° C.,for a period of one hour to seven days, preferably 6 hours, to give amixture of the 4"-O-heteroarylalkyl, 4"-O-heteroarylalkenyl, or4"-O-heteroarylalkynyl-3-hydroxy macrolide 4a', 3"-O-heteroarylalkyl,3"-O-heteroarylalkenyl, or 3"-O-heteroarylalkynyl-4"-hydroxymacrolide4b' and the 3",4"-di-O-heteroarylalkyl,-heteroarylalkenyl or-heteroarylalkynyl macrolide 4c'. Subsequently, a solution of4"-O-heteroaryl, 4"-O-heteroarylalkyl, 4"-O-heteroarylalkenyl or4"-O-heteroarylalkynyl-3-hydroxy macrolide 4a (from Reaction Scheme B or4a', or 3"-O-heteroaryl-, 3"-O-heteroarylalkyl, 3"-O-heteroarylalkenyl,3"-O-heteroarylalkynyl-4"-hydroxymacrolide 4b from Reaction Scheme B or4b' can be treated with an arylalkyl, alkenyl or alkynyltrichloroacetimidate by procedures described above.) to give macrolides5a' or 5b'.

The procedures described in Reaction Schemes C and D may optionally beconducted by following the procedures of Reaction Scheme E or F.Alternatively, the procedures described in Reaction Scheme F may beperformed.

In any of the aforementioned Reaction Schemes, the macrolide (wherein R¹and/or R² contains an alkenyl, substituted alkenyl, alkynyl orsubstituted alkynyl and wherein R³ is hydroxy or C₁₋₆ alkoxy, R⁴ ishydrogen, or R³ and R⁴ taken together form a double bond) can be reducedwith tri-n-butyltin hydride in the presence oftetrakis(triphenylphosphine) palladium (O) catalyst and acetic acid inan organic solvent such as toluene or tetrahydrofuran at or near roomtemperature for about 2 to 10 hours to give the reduced macrolide.

The procedures described in Reaction Scheme F may be conducted on themono-substituted products of Reaction Scheme B (and visa versa) toobtain the mixed disubstituted compounds. In fact, within ReactionSchemes B and F, treatment of the mono-substituted product with adifferent reagent will afford the mixed disubstituted compounds.

Reaction Scheme F:

Protection of the C-3", C-4" and/or the C-14 hydroxyl group(s) may beaccomplished by methods known in the prior art for compounds of FormulaII such as by treatment with: 2,6-lutidine and triisopropylsilyltrifluoromethanesulfonate in a solution of methylene chloride;2,6-lutidine and t-butyldimethylsilyl trifluoromethanesulfonate in asolution of methylene chloride; pyridine and acetic anhydride in asolution of methylene chloride; pyridine and benzoyl chloride in asolution of dichloromethane; pyridine and p-nitrobenzoyl chloride in asolution of dichloromethane; imidazole and t-butyldiphenylsilyl chloridein a solution of methylene chloride; and the like. For example, as shownin Reaction Scheme F, the C-4", 14-dihydroxy-C-3"-methoxy macrolide 7may be protected at C-14 as the t-butyldimethylsilyl ether by treatmentwith t-butyldimethylsilyl trifluoromethanesulfonate in methylenechloride to give the C-4", 14-di-O-TBDMS macrolide. Treatment withtoluenesulfonic acid in methanol results in selective removal of theC-4" silyl ether to give the C-14-O-TBDMS macrolide 8.

Reaction Scheme G:

As shown in Reaction Scheme G, the 4"-hydroxy-3"-R² O macrolide 9 oralternatively the 3"-hydroxy-4"-R² O macrolide (not depicted) (whereinR³ is protected hydroxy or hydrogen) may be reacted with an alkenyltrichloroacetimidate (wherein alkenyl is C₃₋₁₀ alkenyl) under conditionsdescribed in Reaction Scheme E to give the O-alkenyl macrolide 10.Treatment with a stoichiometric amount of osmium tetroxide in an inertorganic solvent, such as diethyl ether or tetrahydrofuran, in thepresence of an amine base, such as pyridine, at or near room temperaturegives the corresponding glycol 11 (wherein A is C₁₋₈ alkyl). Treatmentof glycol 11 with sodium metaperiodate in a solution oftetrahydrofuran/water gives aldehyde 12. Alternatively, the alkenylmacrolide 10 may be treated with sodium metaperiodate in the presence ofa catalytic amount of osmium tetroxide in an organic solvent to give thealdehyde directly. Aldehyde 12 can be further oxidized to carboxylicacid 13 by any number of methods commonly used.

Reaction Scheme H:

A variety of compounds may be prepared from aldehyde 12 as illustratedin Reaction Scheme H. Aldehyde 12 may be reacted with a primary orsecondary amine, HNR⁶ R⁷ (wherein R⁶ and/or R⁷ are as defined andcontain(s) a heteroaryl group) in an organic solvent such astetrahydrofuran to give an imine which is reduced in situ with a hydridereducing agent, such as sodium cyanoborohydride, to give macrolide 14bearing an aminoalkoxy functionality at C-4". Aldehyde 12 may also bereduced to the corresponding alcohol 15 by treatment with a hydridereducing agent, such as potassium triphenyl borohydride or sodiumcyanoborohydride in an organic solvent such as tetrahydrofuran. Alcohol15 may be further modified by utilizing the methods of Reaction Scheme B(wherein R¹ is as defined) or Reaction Scheme E to produce macrolide 16.The procedures described in Reaction Scheme H are readily applicable tothe preparation of compounds bearing analagous functionality at C-3".

Reaction Scheme I

Amide derivatives may be prepared from the carboxylic acid 13 asillustrated in Reaction Scheme I. The carboxylic acid 13 may be coupledwith a primary or secondary amine, HNR⁶ R⁷ (wherein R⁶ and/or R⁷ are asdefined and contain(s) a heteroaryl group) by any of the peptidecoupling methods commonly used in the art, such as with BOP reagent orDCC/HOBT.

Reaction Scheme J

A hydroxyl or fluoro group may be introduced at C-20 essentially by theprocedures of Reaction Scheme J. As shown in Reaction Scheme R the4",14-dihydroxy macrolide (or the 14-deoxymacrolide) is protected as thedi(t-butyldimethylsilyl ether) by treatment with t-butyldimethylsilyltriflate in an inert organic solvent such as methylene chloride,chloroform or the like in the presence of a non-nucleophillic base suchas 2,6-lutidine. The diprotected macrolide is oxidized at C-20 asfurther shown in Reaction Scheme J by treatment with selenium dioxide inan alcoholic solvent such as ethanol in the presence of pyridine atsolvent reflux temperature to give the 20-hydroxy macrolide (18). The20-hydroxy macrolide may be further derivatized at C-20 by alkylation,acylation or phosphorylation to give ether, ester or phosphatederivatives by procedures well known to the practitioner of the art. Asfurther illustrated, treatment of the 20-hydroxy 4",14-di-OTBS macrolidewith diethylaminosulfur trifluoride in an inert organic solvent such asmethylene chloride, chloroform or the like at a temperature of about 0°C. to -90° C., preferably about -78° C., gives the 20-fluoro 4",14-di-OTBS macrolide (19). Removal of the silyl ether protecting groupsby treatment with hydrogen fluoride-pyridine complex in tetrahydrofurangives the 20 -fluoro 4",14-dihydroxy macrolide which may be furtherderivatized by any of the methods previously described. Reaction SchemeJ may also be performed on the 3", 4", 14-trihydroxy macrolide to givethe 20-fluoro 3", 4", 14-trihydroxy macrolide. The procedures ofReaction Scheme J may be conducted prior to, concurrent with, orsubsequent to the procedures of Reaction Schemes A-I.

The object compounds of Formula I obtained according to the reactions asexplained above can be isolated and purified in a conventional manner,for example, extraction, precipitation, fractional crystallization,recrystallization, chromatography, and the like.

In the compounds of Formula I, OR¹ may be substituted at C-4" or C-3",or both C-4" and C-3" (wherein R² is independently selected from thedefinitions of R¹), but it is preferred that --OR¹ is substituted atC-4".

It is to be noted that in the aforementioned reactions and thepost-treatment of the reaction mixture therein, the stereoisomer(s) ofstarting and object compounds due to asymmetric carbon atom(s) or doublebond(s) of the object compounds of Formula I may occasionally betransformed into the other stereo isomer(s), and such cases are alsoincluded within the scope of the present invention.

In the present invention, compounds with asymmetric centers may occur asracemates, as diastereomeric mixtures and as individual diastereomers,with all isomeric forms of the compounds being included in the presentinvention. These may be prepared by methods such as those disclosed inpublications which describe synthetic routes to fragments of themacrolide FR-900506 and the total synthesis of the macrolide FR-900506itself (J. Am. Chem. Soc. 1989, 111, 1157; J. Am. Chem. Soc. 1990, 112,2998; J. Org. Chem. 1990, 55, 2786; J. Am. Chem. Soc. 1990, 112, 5583.Tetrahedron Lett. 1988, 29, 277; Tetrahedron Lett. 1988, 29, 281;Tetrahedron Lett. 1988, 29, 3895; J. Org. Chem. 1988, 53, 4643;Tetrahedron Lett. 1988, 29, 4245; Tetrahedron Lett. 1988, 29, 4481; J.Org. Chem. 1989, 54, 9; J. Org. Chem. 1989, 54, 11; J. Org. Chem. 1989,54, 12; J. Org. Chem. 1989, 54, 15; J. Org. Chem. 1989, 54, 17;Tetrahedron Lett. 1989, 30, 919; Tetrahedron Lett. 1989, 30, 1037; J.Org. Chem. 1989, 54, 2785; J. Org. Chem. 1989, 54, 4267; TetrahedronLett. 1989, 30, 5235; Tetrahedron Lett. 1989, 30, 6611; TetrahedronLett. 1989, 30, 6963; Synlett 1990, 38; J. Org. Chem. 1990, 55, 2284; J.Org. Chem. 1990, 55, 2771; J. Org. Chem. 1990, 55, 2776; TetrahedronLett. 1990, 31, 1439; Tetrahedron Lett. 1990, 31, 1443; TetrahedronLett. 1990, 31, 3007; Tetrahedron Lett. 1990, 31, 3283, 3287).

The compounds of the present invention are capable of forming salts withvarious inorganic and organic acids and bases and such salts are alsowithin the scope of this invention. Examples of such acid addition salts(which are negative counterions defined herein as M⁻) include acetate,adipate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, ethanesulfonate, fumarate, hemisulfate,heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,methanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, pivalate,propionate, succinate, tartrate, tosylate, and undecanoate. Base salts(which are positive counterions defined herein as M⁺) include ammoniumsalts, alkali metal salts such as sodium, lithium and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases such as dicyclohexylamine salts,N-methyl-D-glucamine, and salts with amino acids such as arginine,lysine and so forth. Also, the basic nitrogen-containing groups may bequaternized with such agents as: lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chainhalides such as decyl, lauryl, myristyl and stearyl chlorides, bromidesand iodides; aralkyl halides like benzyl bromide and others. Thenon-toxic physiologically acceptable salts are preferred, although othersalts are also useful, such as in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting thefree base form of the product with one or more equivalents of theappropriate acid in a solvent or medium in which the salt is insoluble,or in a solvent such as water which is removed in vacuo or by freezedrying or by exchanging the anions of an existing salt for another anionon a suitable ion exchange resin.

C. Utility of the compounds within the scope of the invention

The compounds of Formula I may be employed as immunosuppressants orantimicrobial compounds by methods and in dosages known in the prior artfor compounds of Formula II. These compounds possess pharmacologicalactivity such as immunosuppressive activity, antimicrobial activity, andthe like, and therefore are useful for the treatment and prevention ofthe resistance to transplantation or transplantation rejection of organsor tissues (such as heart, kidney, liver, lung, bone marrow, cornea,pancreas, intestinum tenue, limb, muscle, nervus, medulla ossium,duodenum, small-bowel, medulla ossium, skin, pancreatic islet-cell, etc.including xeno transplantation), graft-versus-host diseases by medullaossium transplantation, autoimmune diseases such as rheumatoidarthritis, systemic lupus erythematosis, nephrotic syndrome lupus,Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type Idiabetes mellitus, type II adult onset diabetes, uveitis, nephroticsyndrome, steroid-dependent and steroid-resistant nephrosis,Palmo-planter pustulosis, allergic encephalomyelitis,glomerulonephritis, etc., and infectious diseases caused by pathogenicmicroorganisms.

The compounds of Formula I are also useful for treating inflammatory,proliferative and hyperproliferative skin diseases and cutaneousmanifestations of immunologically-mediated illnesses such as: psoriasis,psoriatic arthritis, atopical dermatitis, contact dermatitis and furthereczematous dermatitises, seborrhoeic dermatitis, Lichen planus,Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria,angioedemas, vasculitides, erythemas, cutaneous eosinophilias, acne,Alopecia areata, eosinophilic fasciitis, and atherosclerosis. Moreparticularly, the compounds of Formula I are useful in hairrevitalizing, such as in the treatment of male or female patternalopecia or alopecia senilis, by providing epilation prevention, hairgermination, and/or a promotion of hair generation and hair growth.

The compounds of Formula I are further useful in the treatment ofrespiratory diseases, for example sarcoidosis, fibroid lung, idiopathicinterstitial pneumonia, and reversible obstructive airways disease,including conditions such as asthma, including bronchial asthma,allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma,particularly chronic or inveterate asthma (for example late asthma andairway hyperresponsiveness), bronchitis and the like. The compounds ofFormula I may also be useful for treating hepatic injury associated withischemia.

The compounds of the invention are also indicated in certain eyediseases such as keratoconjunctivitis, vernal conjunctivitis, uveitisassociated with Behcet's disease, keratitis, herpetic keratitis, conicalcornea, dystorphia epithelialis corneae, corneal leukoma, ocularpemphigus, Mooren's ulcer, Scleritis, Graves' ophthalmopathy, severeintraocular inflammation, and the like.

The compounds of Formula I are also useful for treating multidrugresistance of tumor cells, (i.e. enhancing the activity and/orsensitivity of chemotherapeutic agents), preventing or treatinginflammation of mucosa or blood vessels (such as leukotriene B₄-mediated diseases, gastric ulcers, vascular damage caused by ischemicdiseases and thrombosis, ischemic bowel disease, inflammatory boweldisease (e.g., Crohn's disease and ulcerative colitis) necrotizingenterocolitis), or intestinal lesions associated with thermal burns,cytomegalovirus infection, particularly HCMV infection.

Further, the compounds of Formula I are also useful for treating orpreventing renal diseases including interstitial nephritis,Goodpasture's syndrome, hemolytic-uremic syndrome and diabeticnephropathy; nervous diseases selected from multiple myositis,Guillain-Barre syndrome, Meniere's disease and radiculopathy; endocrinediseases including hyperthyroidism and Basedow's disease; hematicdiseases including pure red cell aplasia, aplastic anemia, hypoplasticanemia, idiopathic thrombocytopenic purpura, autoimmune hemolyticanemia, agranulocytosis and anerythroplasia; bone diseases includingosteoporosis; respiratory diseases including sarcoidosis, fibroid lungand idiopathic interstitial pneumonia; skin diseases includingdermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergicsensitivity and cutaneous T cell lymphoma; circulatory diseasesincluding arteriosclerosis, aortitis syndrome, polyarteritis nodosa andmyocardosis; collagen including scleroderma, Wegener's granuloma andSjogren's syndrome; adiposis; eosinophilic fasciitis; periodontaldisease; nephrotic syndrome; hemolytic-uremic syndrome; and musculardystrophy.

Further, the compounds of the invention are indicated in the treatmentof diseases including intestinal inflammations/allergies such as Coeliacdisease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn'sdisease and ulcerative colitis; and food related allergic diseases whichhave symptomatic manifestation remote from the gastrointestinal tract,for example migraine, rhinitis and eczema.

The compounds of the invention also have liver regenerating activityand/or activity in stimulating hypertrophy and hyperplasia ofhepatocytes. Therefore, they are useful for the treatment and preventionof hepatic diseases such as immunogenic diseases (e.g. chronicautoimmune liver diseases including autoimmune hepatitis, primarybiliary cirrhosis and sclerosing cholangitis), partial liver resection,acute liver necrosis (e.g. necrosis caused by toxins, viral hepatitis,shock or anoxia), B-virus hepatitis, non-A/non-B hepatitis andcirrhosis.

The compounds of the invention are also indicated for use asantimicrobial agents, and thus may be used in the treatment of diseasescaused by pathogenic microorganisms and the like.

The compounds of Formula I may also act as antagonists of macrocyclicimmunosuppressive compounds, including derivatives of12-(2'-cyclohexyl-1'-methylvinyl)-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene, and so be useful in the treatment of immunodepression(such as AIDS, cancer, senile dementia, trauma (including wound healing,surgery and shock), chronic bacterial infection and certain centralnervous system disorders), overdosages or toxicity of suchimmunosuppressive compounds, and as an adjunct to the administration ofan antigen in vaccination.

The pharmaceutical compositions of this invention can be used in theform of a pharmaceutical preparation, for example, in solid, semisolidor liquid form, which contains one or more of the compounds of thepresent invention, as an active ingredient, in admixture with an organicor inorganic carrier or excipient suitable for external, enteral orparenteral applications. The active ingredient may be compounded, forexample, with the usual nontoxic, pharmaceutically acceptable carriersfor tablets, pellets, capsules, suppositories, solutions, emulsions,suspensions, and any other form suitable for use. The carriers which canbe used are water, glucose, lactose, gum acacia, gelatin, mannitol,starch paste, magnesium trisilicate, talc, corn starch, keratin,colloidal silica, potato starch, urea and other carriers suitable foruse in manufacturing preparations, in solid, semisolid, or liquid form,and in addition auxiliary, stabilizing, thickening and coloring agentsand perfumes may be used. For example, the compounds of Formula I may beutilized with hydroxypropyl methylcellulose essentially as described inU.S. Pat. No. 4,916,138, issued Apr. 10, 1990, or with a surfactantessentially as described in EPO Publication 0,428,169. Oral dosage formsmay be prepared essentially as described by T. Hondo, et al.,Transplantation Proceedings, 1987, XIX, Supp. 6, 17-22. Dosage forms forexternal application may be prepared essentially as described in EPOPublication 0,423,714. The active object compound is included in thepharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of diseases.

For the treatment of these conditions and diseases caused byimmunoirregularity a compound of Formula I may be administered orally,topically, parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques.

For the treatment of reversible obstructive airways disease, it ispreferable that the compound of Formula I be administered by inhalationto the lung, especially in the form of a powder.

For modifying the activity and/or toxicity of FK-506-typeimmunosuppressants, a compound of Formula I may be administered priorto, in conjunction with or subsequent to the administration of anFK-506-type of a compound.

The compounds of Formula I may optionally be employed in co-therapy withanti-proliferative agents. Particularly preferred is co-therapy with anantiproliferative agent selected from the group consisting of:azathioprine, brequinar sodium, deoxyspergualin, mizaribine,mycophenolic acid morpholino ester, cyclosporin, and rapamycin.

Dosage levels of the compounds of the present invention are of the orderfrom about 0.005 mg to about 50 mg per kilogram of body weight per day,preferably from about 0.1 mg to about 10 mg per kilogram of body weightper day, are useful in the treatment of the above-indicated conditions(from about 0.7 mg to about 3.5 mg per patient per day, assuming a 70 kgpatient). In addition, the compounds of the present invention may beadministered on an intermittent basis; i.e. at daily, semiweekly,weekly, semi-monthly or monthly intervals.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 0.5 mg to 5 gm of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally comprise from about 0.01 mg to about 500 mg, and preferablyabout 0.5 mg to about 100 mg of active ingredient. For externaladministration the compound of Formula I may be formulated within therange of, for example, 0.0001% to 60% by weight, preferably from 0.001to 10% by weight, and most preferably from about 0.005 to 0.8% byweight.

It will be understood, however, that the specific dose level for anyparticular patient will depend on a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

The following examples are given for the purpose of illustrating thepresent invention and shall not be construed as being limitations on thescope or spirit of the instant invention.

PREPARATION OF STARTING INTERMEDIATES17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

A solution of 500 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone in 7 ml of benzene was treated with10 mg of p-toluenesulfonic acid and the solution was heated at 60° C.for two hours. The reaction mixture was quenched into saturated sodiumbicarbonate solution and extracted with ethyl acetate. The combinedorganic layers were washed with water and saturated sodium chloridesolution, dried with anhydrous magnesium sulfate and concentrated. Theresidue was chromatographed on silica gel (66% ethyl acetate: 33%hexane: 1% methanol) to give 350 mg of product. This material wasdissolved in 10 ml of ethyl acetate and treated with 15 mg of 5% Rh/C. Aballoon containing hydrogen was placed over the reaction mixture and themixture stirred until the reaction was complete. The mixture wasfiltered through diatomaceous earth, concentrated and the residuesubjected to chromatography (75 % CH₂ Cl₂ : 5% MeOH: 20% Hexane) to give294 mg of product.

17-Ethyl-1-hydroxy-12-[2'-(4",3"-dihydroxyoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9]octacos-18-ene-2,3,10,16-tetraone

A solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (210 mg) and a catalytic amount ofp-toluenesulfonic acid in 40 ml of benzene was refluxed for 4 hoursunder a nitrogen atmosphere. The solvent was removed under reducedpressure and the dark residue was purified by chromatography (silicagel, 7% i-propanol/CH₂ Cl₂) to give17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-14,18-diene-2,3,10,16-tetraone (180 mg) as a white solid. Thismaterial was dissolved in ethanol (20 ml) and treated with 5% Rh/C (40mg). Hydrogen was introduced via balloon for 30 min. and the mixture wasfiltered through celite. Removal of solvent followed by chromatography(silica gel) gave 172 mg of the title compound. Mass, ¹ H and ¹³ C NMRdata were consistent with the title structure.

17-Ethyl-1-hydroxy-12-[2'-(4"-triisopropylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-14-triisopropylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a cooled solution (0° C.) of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9]octacos-18-ene-2,3,10,16-tetraone (120 mg) in dry methylene chloride(15 ml) was added 2,6-lutidine (64.3 mg) followed by triisopropylsilyltrifluoromethanesulfonate (184 mg). Reaction temperature was raised tor.t. and stirred overnight under nitrogen atmosphere. The reaction wasquenched with 10 ml of water and extracted with ethyl acetate. Organiclayer was washed (water, sat'd NaHCO₃, sat'd NaCl) and dried (anhydrousMgSO₄). Removal of solvent followed by chromatography on silica gel (70%hexane/ethyl acetate) gave 150 mg of product. MASS: (FAB) 1110 (M⁺ +Li).

17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-14-triisopropylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

The title compound from the previous preparation (680 mg) was dissolvedin methylene chloride (45 ml) and 10% solution of p-toluenesulfonic acidin methanol (45 ml) was added with stirring. The mixture was stirred atroom temperature and the progress was followed by tlc analysis. After 4hr, reaction was quenched with sat'd sodium bicarbonate and extractedwith ethyl acetate three times. Normal work-up and removal of solventfollowed by purification on silica gel column (80% ethyl acetate/hexane)gave 560 mg of the product (2a) as a white solid. MASS: (FAB) 954 (M⁺+Li).

17-Ethyl-1-hydroxy-12-[2'-(4"-t-butyldimethylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyldimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatri-cyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a cooled solution (0°C.) of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (1a) (395 mg) in dry methylenechloride (15 ml) was added 2,6-lutidine (160 mg) followed byt-butyldimethylsilyl triflouromethanesulfonate (250 mg). Reactiontemperature was raised to r.t. and stirred under nitrogen atmosphere.After 6 hr, the reaction was quenched with 10 ml of water and extractedwith ethyl acetate. Organic layer was washed (water, saturated NaHCO₃,saturated NaCl) and dried (anhydrous MgSO₄). Removal of solvent underreduced pressure gave 500 mg of crude product. MASS: (FAB) 1023 (M⁺+Li).

17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyldimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

The product from the previous example (500 mg) was dissolved inacetonitrile (20 ml) and 100 ml of hydrogen fluoride (48%) was added.Reaction was stirred for 20 minutes at room temperature, quenched withsaturated sodium bicarbonate, then extracted with ethyl acetate. Removalof solvent in vacuo followed by chromatography on silica gel (80% ethylacetate/hexane) gave 300 mg of product (Mass, ¹ H and ¹³ C NMR dataconsistent with the title compound.

17-Ethyl-1-hydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(3.01 g) in dry methylene chloride (70 ml) was added an excess ofimidazole (809 mg) followed by tert-butyldimethylsilyl chloride (716mg). After 3 days of stirring at room temperature, the mixture wasdiluted with ethyl acetate which in turn was washed with 1N HCl,saturated sodium bicarbonate and brine, dried over magnesium sulfate andpurified by flash chromatography (ethyl acetate:hexane (1:3)) to givethe title compound (941 mg). ¹ H NMR consistent with the desiredstructure.

17-Ethyl-1-hydroxy-12-[2'-(4"-(tert-butyldimethylsilyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methlvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg) in dry methylene chloride (3ml) was added an excess of 2,6-lutidine (45 μl) and the mixture wasstirred at room temperature. After 10 minutes, tert-butyldimethylsilyltrifluoromethanesulfonate (64 μl) was added by syringe. After 15 minutesthe reaction mixture was diluted with ethyl acetate, extracted fromsaturated bicarbonate, washed with brine and the organic phase driedover magnesium sulfate. Removal of solvent in vacuo and flashchromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol)gave the title compound (235 mg).

(¹ H NMR consistent with the desired structure).

17-Ethyl-1,20-dihydroxy-12-[2'-(4"-tert-butyldimethylsilyloxy)-3"-methoxycyclohexyl)-4"1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-ethyl-1-hydroxy-12-[2'-(4"-(tert-butyldimethylsilyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (235 mg) in 95% ethanol (2.2 ml) wasadded 53 μl of pyridine followed by selenium dioxide (58 mg). The flaskwas fitted with a water condenser and heated to 70° C. on a mantle.After 20 hours the mixture was cooled to room temperature filteredthrough diatomaceous earth and the filtrate poured into a saturatedsodium bicarbonate solution. This was extracted with ethyl acetate,washed with brine and dried over magnesium sulfate. The solution wasconcentrated and purified by flash chromatography on silica gel (ethylacetate:hexane (1:2)+1% methanol) to give the title compound (89 mg).

(¹ H NMR consistent with the desired structure).

17-Ethyl-20-fluoro-1-hydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy--13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

A solution of17-ethyl-20-dihydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (30.5 mg) in methylene chloride (0.5ml) was cooled to -78° C. in a dry ice/isopropanol bath. To this stirredsolution, diethylaminosulfur trifluoride (4.5 μl) was added. After 3minutes, saturated sodium bicarbonate (500 μl) was added followed byethyl acetate (2 ml) and the mixture was warmed to room temperature.Extraction from ethyl acetate, drying over magnesium sulfate andpurification by flash chromatography on silica gel (ethyl acetate:hexane(1:2)+1% MeoH) gave the title compound (22 mg).

(¹ H NMR consistent with the desired structure).

17-Ethyl-1,20-dihydroxy-12[2'-(4"-(hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10.16-tetraone

To a solution of17-ethyl-1,20-dihydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,-27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,13,10.6-tetraone (7 mg) in acetonitrile (0.3 ml) wasadded a solution of 2% hydrogen fluoride in aqueous acetonitrile (100μl), and the mixture stirred at room temperature. After 28 hours thesolution was diluted with ethyl acetate, extracted with saturated sodiumbicarbonate and the organic phase dried by passage through a magnesiumsulfate column. Purification of the concentrate by flash chromatographyon silica gel (ethyl acetate:hexane (2:1)+1% methanol) gave the titlecompound.

17-Ethyl-20-fluoro-1-hydroxy-12-[2'-(4"-(hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10.16-tetraone

To a solution of17-ethyl-20-fluoro-1-hydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10.16-tetraone (7 mg) in acetonitrile (0.3 ml) wasadded a solution of 2% hydrogen fluoride in aqueous acetonitrile (100μl), and the mixture stirred at room temperature. After 2 hours thesolution was diluted with ethyl acetate, extracted with saturated sodiumbicarbonate and the organic phase dried by passage through a magnesiumsulfate column. Purification of the concentrate by flash chromatographyon silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the titlecompound. MASS: (FAB) 816 (M+Na).

partial ¹³ C NMR δ: 211.5 (C-16); 196.1 (2) 169.3 (10); 165.0 (3); 138.1(C-19); 135.8 (C-1'); 121.0 (C-18' major); 84.1 (C-3"); 43.1 (C-15);26.0 (C-21).

17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone ALTERNATE ROUTE

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'--methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (5.15 gm, 0.065 mol) in glacialacetic acid (500 ml) at room temperature, was added a solution ofselenium dioxide (9.27 gm, 0.083 mol) in H₂ O (90 ml). The reactionmixture was stirred at room temperature for 41 hours whereupon, it waspoured into a stirred mixture of H₂ O (3 L) and celite. After stirringfor 15 minutes, the mixture was filtered through a pad of celite andextracted with diethyl ether (1×2 L, 2×1 L). The organic fractions werewashed with saturated sodium bicarbonate and brine, dried over magnesiumsulfate, filtrated and evaporated in vacuo. The product was purified bychromatography (silica, acetone:hexanes 2:5) to give the title compoundMASS and ¹ H NMR were consistent with the structure.

EXAMPLE 117-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-furanyl)methoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(63 mg in 1.0 ml methylene chloride) furfuryl trichloroacetimidate (39μl neat) was added and the reagents allowed to mix for 5 minutes.Camphorsulfonic acid (3.7 mg) was added and the mixture stirred at roomtemperature. After 4.5 hours the reaction was quenched by the additionof saturated sodium bicarbonate and extracted with ethyl acetate (3×5ml). The combined organics were washed with brine and dried overmagnesium sulfate. Purification of the concentrate by flashchromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol)gave the title compound (20 mg). MAS: (FAB) 878 (M+Li). Partial ¹ H NMRδ: 7.38(brs, 1H); 6.30(m, 3H); 5.32M, 5.19m(brd J=3 Hz, 1H); 4.83m, 4.21M(brs, 1H); 4.62(dd J=15Hz, 2H); 4.41(brd J=14 Hz, 1H).

EXAMPLES 2 and 317-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-furanyl)methoxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(2-furanyl)methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(52 mg in 0.9 ml methylene chloride) furfuryl trichloroacetimidate (20μl neat) was added and the reagents allowed to mix for 5 minutes.Camphorsulfonic acid (2 mg) was added and the mixture stirred at roomtemperature. After 3.5 hours the reaction was quenched by the additionof saturated sodium bicarbonate and extracted with ethyl acetate (3×5ml). The combined organics were washed with brine and dried overmagnesium sulfate. Purification of the concentrate by flashchromatography on silica gel (ethyl acetate: hexane (1:1)+1% methanol)gave the title compounds (16 mg 4" ether; 13 mg 3" ether).

4" ether: MASS: (FAB) 864 (M+Li); Partial ¹ H NMR δ: 7.41(brs, 1H);6.30(m, 2H); 5.32M, 5.19m(brd J=3 Hz, 1H); 4.87m, 4.19M(brs, 1H);4.41(brd J=14 Hz, 1H).

3" ether: MASS: (FAB) 864 (M+Li); Partial ¹ H NMR δ: 7.44(brs, 1H);6.37(m, 2H); 5.32M, 5.19m(brd J=3 Hz, 1H); 4.88m, 4.27M(brs, 1H);4.41(brd J=14 Hz, 1H).

EXAMPLE 417-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-thiophene)methoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared essentially as described in Example 1using 2-thiophenylmethyl trichloroacetimidate as the alkylating agent.Partial ¹ H NMR δ: 7.27(m, 1H); 6.96(m, 2H); 5.31M, 5.18m(brd J=3 Hz,1H); 4.81m, 4.22M(brs, 1H); 4.41(brd J=14 Hz, 1H); 3.07(d J=4 Hz, 1H).

EXAMPLES 5 and 617-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-thiophene)methoxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(2-thiophene)methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

The title compounds were prepared essentially as described in Examples 2and 3 using 2-thiophenylmethyl trichloroacetimidate as the alkylatingagent.

4" ether: MASS: (FAB) 896 (M+Na); Partial ¹ H NMR δ: 7.29(m, 1H);6.97(m, 2H); 5.13M, 5.19m(brd J=3 Hz, 1H); 4.41(brd J=14 Hz, 1H); 3.04(dJ=4 Hz, 1H); 2.63M, 2,61m(s, 1H);

3" ether: MASS: (FAB) 880 (M+Li); Partial ¹ H NMR δ: 7.28 (m, 1H); 6.97(m, 2H); 5.31M, 5.19 m (brd J=3 Hz, 1H); 4.41 (brd J=14 Hz, 1H); 3.08 (dJ=3 Hz, 1H); 2.69 (s, 1H).

EXAMPLES 7 and 817-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3-thiophene)methoxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(3-thiophene)methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

The title compounds were prepared essentially as described in Examples 2and 3 using 3-thiophenylmethyl trichloroacetimidate as the alkylatingagent.

4" ether: MASS: (FAB) 880 (M+Li); Partial ¹ H NMR δ: 7.30 (m, 1H); 7.04(m, 2H); 5.31M, 5.19 m (brd J=3 Hz, 1H); 4.89 m, 4.19M (s, 1H); 4.41(brd J=14 Hz, 1H); 3.04 (d J=4 Hz, 1H);

3" ether: MASS: (FAB) 880 (M+Li); Partial ¹ H NMR δ: 7.28 (m, 2H); 7.05(dd, J=5, 2 Hz, 1H); 5.31M, 5.19 m (brd J=3 Hz, 1H); 4.83 m, 4.25M (brs,1H); 4.41 (brd J=14 Hz, 1H); 3.06 (d J=3 Hz, 1H); 2.69 (s, 1H).

EXAMPLE 917-Ethyl-1,14-dihydroxy-12-[2'-(4"-(benzothien-2-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(benzothien-2-yl)bismuthine (100 mg., 0.164mmol.) in CH₂ Cl₂ (2 mL.) was added peracetic acid (0.050 mL., 0.224mmol., 32% in acetic acid) followed in 10 minutes by 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclo-hexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9]octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.126 mmol.) and Cu(OAc)₂(15 mg., 0.083 mmol.). The reaction mixture was stirred for 16 hours atroom temperature. The reaction was then quenched with saturated aqueousNaHCO₃ and the mixture extracted 3× with CH₂ Cl₂. The extracts werecombined, dried with Na₂ SO₄, filtered, and concentrated in vacuo. Theproduct was isolated and purified by preparative TLC 3× on silica gel(3:1, hexane/acetone) to give 23 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(benzothien-2-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone.

EXAMPLE 1017-Ethyl-1,14-dihydroxy-12-[2'-(4"-(thien-2-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(thien-2-yl)bismuthine (80 mg., 0.175 mmol.)in CH₂ Cl₂ (2 mL.) was added peracetic acid (0.060 mL., 0.253 mmol., 32%in acetic acid) followed in 15 minutes by17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.126 mmol.) and Cu(OAc)₂(10 mg., 0.055 mmol.). The reaction mixture was allowed to stir at roomtemperature for 3 days. The reaction was quenched with saturated aqueousNaHCO₃, and the mixture extracted with CH₂ Cl₂. The extracts werecombined, dried with Na₂ SO₄, filtered and concentrated in vacuo. Theproduct was isolated and purified by preparative TLC 2× on silica gel(2:1, hexane/acetone) to give 36 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(thien-2-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone.

EXAMPLE 1117-Ethyl-1,14-dihydroxy-12-[2'-(4"-5-indolylaminocarbonylmethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone STEP 11A17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(2.0 g) in dry methylene chloride (25 ml) was added an excess of2,6-lutidine (1.2 ml) and the mixture was stirred at room temperature.After 10 minutes, tert-butyldimethylsilyl trifluoromethanesulfonate (1.8ml) was added via syringe. After 1 hour the reaction mixture was dilutedwith ethyl acetate, washed with 1N HCl, water, saturated sodiumbicarbonate and brine. The organic phase was dried over magnesiumsulfate. Removal of the solvent in vacuo and flash chromatography onsilica gel (ethyl acetate:hexane (1:6)+1% methanol) gave the titlecompound (2.37 g). ¹ H NMR consistent with the desired structure.

STEP 11B17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(2.37 g) (STEP 11A) in dry methylene chloride (25 ml) was added asolution of 10% p-toluenesulfonic acid in methanol (25 ml), and themixture was stirred at room temperature. After 10 minutes, the mixturewas cooled to 0° C. and quenched with saturated sodium bicarbonate. Themixture was diluted with ethyl acetate and the layers were separated.The organic layer was washed with saturated sodium bicarbonate and brineand dried over magnesium sulfate. Purification of the concentrate byflash chromatography on silica gel (ethyl acetate:hexane (1:2)+1%methanol) gave the title compound (2.1 g). ¹ H NMR consistent with thedesired structure.

STEP 11C17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(2.1 g) (STEP 11B) in 24 ml 33% methylene chloride in cyclohexane, wasadded allyl trichloroacetimidate (938 mg neat) and the reaction mixturewas allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (41 μlneat) was added slowly via syringe and the mixture stirred at roomtemperature. After 24 hours, the reaction mixture was diluted with ethylacetate and washed with saturated sodium bicarbonate, water and brine.The organic layer was dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:5))+1% methanol) gave the title compound (1.03 g). ¹ H NMR consistentwith the desired structure.

STEP 11D17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2,3-dioxy-1-propoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(STEP 11C) (1.03 g) in 22 ml tetrahydrofuran was addedN-methylmorpholine N-oxide (883 mg) followed by 0.25M osmium tetraoxidesolution in THF (871 μl), and the mixture was stirred at roomtemperature. After 3 hours, the reaction was quenched by the addition of20% sodium bisulfite (20 ml), and the precipitate was filtered throughCelite and rinsed with ethyl acetate. The combined filtrate was washedwith 20% sodium bisulfite (2×), saturated sodium bicarbonate and brineand dried over magnesium sulfate. The concentrate was purified by flashchromatography on silica gel (ethyl acetate:hexane (2:1)+1% methanol) togive the title compound (705 mg). ¹ H NMR consistent with the desiredstructure.

STEP 11E17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2,3-dioxy-1-propoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(1.56 g) (STEP 11D) in 20% aqueous tetrahydrofuran (20 ml) was addedsodium metaperiodate (510 mg) and the mixture stirred vigorously for 30minutes. At this time an additional 170 mg of sodium metaperiodate wereadded. After 30 minutes the mixture was diluted with ethyl acetate,filtered through Celite and the residue rinsed with ethyl acetate. Theorganic portion was washed with saturated sodium bicarbonate and brine,dried over magnesium sulfate and purified by flash chromatography onsilica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the titlecompound (1.45 g). ¹ H NMR consistent with the desired structure.

STEP 11F17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(311 mg) (STEP 11E) in tert-butanol (6.6 ml) and 2-methyl-2-butene (1.65ml) was added sodium chlorite (273 mg) and sodium dihydrogen phosphate(272 mg) in water (2.7 ml) slowly. After 2 hours, the solvent wasremoved in vacuo, and the resulting residue was dissolved in water andacidified to pH 3 with 1N HCl. The aqueous portion was extracted withethyl acetate (3×10 ml) and the combined organic portion was washed withbrine. This was dried over magnesium sulfate and purified by flashchromatography on silica gel (2% methanol in methylene chloride followedby 2% methanol in methylene chloride+0.5% acetic acid) to give the titlecompound (255 mg). ¹ H NMR consistent with the desired structure.

STEP 11G17-Ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-5-indolylamino-carbonylmethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(150 mg) (STEP 11F) in methylene chloride (1.6 ml) was addedbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(103 mg) followed by triethylamine (43 μl). After 10 minutes,5-aminoindole (43 mg) was added to the reaction mixture and stirred for1 hour. The mixture was diluted with ethyl acetate and washed with 1NHCl, water, saturated sodium bicarbonate and brine, respectively. Theorganic portion was dried over magnesium sulfate and purified by flashchromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) togive the title compound (138 mg). ¹ H NMR consistent with the desiredstructure.

STEP 11H17-Ethyl-1,14-dihydroxy-12-[2'-(4"-5-indolylamino-carbonylmethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-5-indolylaminocarbonylmethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo]22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(138 mg in 1 ml tetrahydrofuran contained in a polypropylene vial) wasadded 200 μl of a solution of hydrogen fluoride-pyridine complex (40% in(2:1) tetrahydrofuran:pyridine), and the mixture was stirred at roomtemperature. After 2 days, the reaction was quenched by the carefuladdition of saturated sodium bicarbonate and extracted with ethylacetate. The combined organic portion was washed with brine, dried overmagnesium sulfate, concentrated in vacuo and purified by flashchromatography (ethyl acetate:hexane (1:1)+1% methanol) to give thetitle compound. MASS (FAB) 971 (M+Li); partial ¹ H NMR δ: 9.52 (brs,1H); 8.15 (brs, 1H); 7.91 (s, 1H); 7.30 (s, 2H); 7.16 (dd, J=3,3 Hz,1H); 6.49 (dd, J=,3 Hz, 1H); 4.41 (brd, J=14 Hz, 1H).

EXAMPLE 1217-Ethyl-1-hydroxy-12-[2'-(4"-(methyl-N-tryptophanylcarbonylmethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,-10,16-tetraone STEP 12A17-Ethyl-1-hydroxy-12-[2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,-21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.-0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(510 mg) in 6.6 ml 33% methylene chloride in cyclohexane, was addedallyl trichloroacetimidate (266 mg neat) and the reaction mixture wasallowed to mix for 5 minutes. Trifluoromethanesulfonic acid (12 μl neat)was added slowly via syringe and the mixture stirred at roomtemperature. After 24 hours the reaction mixture was diluted with ethylacetate and washed with saturated sodium carbonate, water and brine. Theorganic layer was dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate: hexane(1:9))+1% methanol) gave the title compound (434 mg). ¹ H NMR consistentwith the desired structure.

STEP 12B17-Ethyl-1-hydroxy-12-[2'-(4"-(2,3-dioxy-1-propoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-allyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(434 mg)(STEP 12A) in 15 ml tetrahydrofuran, was addedN-methylmorpholine N-oxide (431 mg) followed by 0.25M osmium tetraoxidesolution in THF (425 μl), and the mixture was stirred at roomtemperature. After 4.5 hours, the reaction was quenched by the additionof 20% sodium bisulfite, and the precipitate was filtered through Celiteand rinsed with ethyl acetate. The combined filtrate was washed with 20%sodium bisulfite (2×), saturated sodium bicarbonate and brine and driedover magnesium sulfate. The concentrate was purified by flashchromatography on silica gel (ethyl acetate:hexane (3:1)+1% methanol) togive the title compound (177 mg). ¹ H NMR consistent with the desiredstructure.

STEP 12C17-Ethyl-1-hydroxy-12-[2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,-21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-(2,3-dioxy-1-propoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,-10,16-tetraone(177 mg)(STEP 12B) in 20% aqueous tetrahydrofuran (2 ml) was addedsodium metaperiodate (67 mg) and the mixture stirred vigorously for 30minutes. At this time an additional 20 mg of sodium metaperiodate wereadded. After 30 minutes the mixture was diluted with ethyl acetate,filtered through Celite and the residue rinsed with ethyl acetate. Theorganic portion was washed with saturated sodium bicarbonate and brine,dried over magnesium sulfate and purified by flash chromatography onsilica gel (ethyl acetate:hexane (2:3)+1% methanol) to give the titlecompound (157 mg). ¹ H NMR consistent with the desired structure.

STEP 12D17-Ethyl-1-hydroxy-12-[2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-ethanaloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(157 mg) (STEP 12C) in tert-butanol (4 ml) and 2-methyl-2-butene (1 ml)was added sodium chlorite (159 mg) and sodium dihydrogen phosphate (159mg) in water (1.6 ml) slowly. After 1 hour, the solvent was removed invacuo, and the resulting residue was dissolved in water and acidified topH 3 with 1N HCl. The aqueous portion was with ethyl acetate (3×10 ml),and the combined organic portion was washed with brine. It was driedover magenesium sulfate and purified by flash chromatography on silicagel (2% methanol in methylene chloride followed by 2% methanol inmethylene chloride+0.5% acetic acid) to give the title compound (114mg). ¹ H NMR consistent with the desired structure.

STEP 12E17-Ethyl-1-hydroxy-12-[2'-(4"-methoxy-N-tryptophanylcarbonylmethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-carboxymethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(39 mg)(STEP 12D) in methylene chloride (0.5 ml) was addedbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(31 mg) followed by triethylamine (14 μl). After 10 minutes, tryptophanmethyl ester hydrochloride (24 mg) was added to the reaction mixture andstirred for 1 hour. The mixture was diluted with ethyl acetate andwashed with 1N HCl, water, saturated sodium bicarbonate and brine,respectively. The organic portion was dried over magnesium sulfate andpurified by flash chromatography on silica gel (ethyl acetate:hexane(1:1)+1% methanol) to give the title compound (28 mg). MASS (FAB) 1041(M+Li); Partial ¹ H NMR δ: 8.21 (brs, 1H); 8.04 (brd, J=8 Hz, 1H); 7.56(d, J=8 Hz, 1 H); 7.33 (d, J=8 Hz, 1H); 7.11 (m, 3H); 4.41 (brd, J=14Hz, 1H); 3.64 (s, 3H).

EXAMPLE 1317-Ethyl-1-hydroxy-12-[2'-(4"-3-indolylethylaminocarbonylmethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-carboxymethyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,-10,16-tetraone(13 mg) (STEP 12D) in methylene chloride (150 μl) was addedbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(10.3 mg) followed by triethylamine (4.3 μl). After 10 minutes,tryptamine (5 mg) was added to the reaction mixture and stirred for 1hour. The mixture was diluted with ethyl acetate and washed with 1N HCl,water, saturated sodium bicarbonate and brine, respectively. The organicportion was dried over magnesium sulfate and purified by flashchromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol) togive the title compound (7.5 mg). MASS (FAB) 983 (M+Li); partial ¹ H NMRδ: 8.32 (brs, 1H); 7.89 (m, 1H); 7.58 (d, J=8 Hz 1H); 7.31 (m, 1H); 7.10(m, 3H); 4.51 (brd, J=3 Hz, 1H); 4.41 (brd, J=14 Hz, 1H).

EXAMPLE 14 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone STEP 14A 1-Methyl-5-bromoindole

A mixture of sodium hydroxide (0.4 g., 10 mmol.) in DMSO (20 mL.) washeated to 80°-85° C. for 6 hours to dissolve most of the solids thenallowed to cool to room temperature. To the stirred mixture was added5-bromoindole (2.0 g., 10 mmol.) followed in 1 hour by methyliodide(0.62 mL., 10 mmol.). After stirring for an additional 3 hours thereaction was shown by TLC analysis to be complete. The reaction mixturewas diluted with water then extracted with ether. The extracts werewashed 2× with water, dried with Na₂ SO₄, and concentrated in vacuo togive 2.08 g. of 1-methyl-5-bromoindole as a yellow oil whichcrystallized on standing.

STEP 14B Tri(1-methyl-indol-5-yl)bismuthine

To a solution of 1-methyl-5-bromoindole (5.0 g., 23.8 mmol.) in ether(100 mL.) at -78° C. was added a 1.7M solution of t-butyllithium inpentane (28 mL. 47.6 mmol.). The mixture was stirred at -78° C. for 1hour. To this mixture was then added a solution of bismuth trichloride(2.36 g., 7.5 mmol.) in THF (25 mL.) via syringe. The cooling bath wasmaintained for 2 hours then allowed to warm to room temperatureovernight. In the morning the mixture was quenched with ice water andthe product extracted 2× with toluene. The extracts were combined,washed with water, dried with Na₂ SO₄, and concentrated in vacuo to avolume of about 30 mL. After chilling in the refrigerator for severalhours the solid product was filtered, washed with cold toluene andvacuum dried to give tri(1-methyl-indol-5-yl)bismuthine (1.7 g.) as amustard color solid.

STEP 14C17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-methylindol-5-yl)bismuthine (450 mg.,0.75 mmol.) (STEP 14B) in CH₂ Cl₂ (10 mL.) was added peracetic acid(0.158 mL., 0.75 mmol. 32% in acetic acid) followed in 15 minutes by17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (350 mg., 0.442 mmol.) and Cu(OAc)₂.The mixture was stirred at room temperature for 2 days. The reaction wasquenched with saturated aqueous NaHCO₃ and the product extracted 3× withCH₂ Cl₂. The extracts were combined, dried over anhydrous Na₂ SO₄,filtered, and concentrated in vacuo. The product was isolated andpurified 2× by preparative TLC to give 203 mg. of the title compound asa colorless solid. MASS (FAB), m+Li 927. Partial ¹ H NMR (CDCl₃, 200MHz) δ: 7.19 (bs, 1H); 7.17 (d, J=10 Hz, 1H); 6.98 (d, J=4 Hz, 1H); 6.91(dd, J=3 Hz and 10 Hz, 1H); 6.34 (d, J=4 Hz, 1H); 3.72 (s, 3H); 3.51 (s,3H).

EXAMPLE 1517-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-methylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-methylindol-5-yl)bismuthine (350 mg.,0.584 mmol.) in CH₂ Cl₂ (6 mL.) was added peracetic acid (0.15 mL., 0.74mmol., 32% in acetic acid) followed in 15 minutes by17-ethyl-1,14,20-trihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (250 mg., 0.32 mmol.) and Cu(OAc)₂(35 mg., 0.138 mmol.). The reaction mixture was stirred for 2 days atroom temperature. The reaction was quenched with saturated aqueousNaHCO₃ and the mixture extracted 2× with CH₂ Cl₂. The extracts werecombined, dried with Na₂ SO₄, filtered and concentrated in vacuo. Theproduct was isolated by flash column chromatography on silica gel (3:1hexane/acetone) followed by preparative TLC (3% CH₃ OH in CH₂ Cl₂) togive 111 mg of the title compound. MASS (FAB), M+Li 943. Partial ¹ H NMR(CDCl₃, 200 MHz) δ: 7.21 (bs, 1H); 7.18 (d, J=7.5 Hz, 1H); 6.98 (d, J=3Hz, 1H); 6.94 (dd, J=2.5 Hz and 7.5 Hz, 1H); 6.37 (d, J=3 Hz, 1H); 3.75(s, 3H); 3.59 (s, 3H).

EXAMPLE 1617-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-methylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-methylindol-5-yl)bismuthine (35 mg.,0.058 mmol.) in CH₂ Cl₂ (0.7 mL) was added peracetic acid (0.015 mL.,0.074 mmol., 32% in acetic acid) followed in 15 minutes by17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (25 mg., 0.032 mmol.) and Cu(OAc)₂ (5mg., 0.03 mmol.). The reaction mixture was stirred for 3 days at roomtemperature. The reaction was quenched with saturated aqueous NaHCO₃ andextracted 2× with CH₂ Cl₂. The extracts were combined, dried with Na₂SO₄, filtered and concentrated in vacuo. The product was isolated andpurified by preparative TLC. on silica gel (2:1 hexane/acetone then 5%CH₃ OH in CH₂ Cl₂) to give 10.2 mg of the title compound. Partial ¹ HNMR (CDCl₃, 200 MHz) δ: 7.18 (bs, 1H); 7.16 (d, J=7.5 Hz, 1H); 6.98 (d,J=3 Hz, 1H); 6.92 (dd, J=2.5 Hz and 7.5 Hz, 1H); 6.33 (d, J=3 Hz, 1H);3.64 (s, 3H); 3.51 (s, 3H).

EXAMPLES 17 AND 1817-Ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-(1-N-methylindol-5-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9octacos-18-ene-2,3,10,16-tetraone and17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(1-N-methylindol-5-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-methylindol-5-yl)bismuthine (150 mg.,0.25 mmol.) in CH₂ Cl₂ (2 mL.) was added peracetic acid (0.05 mL., 0.23mmol., 32% in acetic acid) followed in 10 minutes by17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.129 mmol) and Cu(OAc)₂ (20mg., 0.11 mmol.). The reaction mixture was stirred for 2 days at roomtemperature. The reaction was quenched with saturated aqueous NaHCO₃ andthe mixture extracted 2× with CH₂ Cl₂. The extracts were combined, driedwith Na₂ SO₄, filtered and concentrated in vacuo. The products wereseparated and purified 2× by preparative TLC (2:1 hexane/acetone then 5%CH₃ OH in CH₂ Cl₂) to give 19 mg of17-ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-(1-methylindol-5-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone, Partial ¹ H NMR (CDCl₃, 200 MHz) δ:7.19 (d, J=10 Hz, 1H); 7.17 (d, J=2.5 Hz, 1H); 7.00 (d, J=3 Hz, 1H);6.88 (dd, J=2.5 Hz and 10 Hz, 1H); 6.35 (d, J=3 Hz, 1H); 3.73 (s, 3H).and 33 mg of17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(1-methylindol-5-yl)ocycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. Partial ¹ H NMR (CDCl₃, 200 MHz) δ:7.18 (d, J=8 Hz, 1H); 7.16 (d, J=2.5 Hz, 1H); 6.98 (d, J=3 Hz, 1H); 6.88(dd, J=2.5 Hz and 8 Hz, 1H); 6.33 (d, J=3 Hz, 1H); 3.73 (s, 3H).

EXAMPLE 19 Tri (indol-5-yl)bismuthine

A solution of 5-bromoindole (5.0 g., 25.5 mmol.) in ether (50 mL.) wasslowly added, at 0° C., to a slurry of KH (2.8 g., 25 mmol., 35% in oil;washed 3× with hexanes) in ether (40 mL.). The reaction mixture wasstirred for 20 minutes then chilled to -78° C. A precooled solution oft-butyllithium (29.7 mL., 50.5 mmol., 1.7M in pentane) was addeddropwise via syringe to the mixture followed in 40 minutes by a solutionof BiCl₃ (1.89 g., 6.0 mmol.) in THF (25 mL.). The cooling bath wasmaintained for 2 hours then allowed to warm to room temperatureovernight. The reaction was quenched with ice water and extracted 3×with toluene. The extracts were combined, dried with Na₂ SO₄, filteredand concentrated in vacuo. The residue was diluted with 75 mL. oftoluene then stored at 4° C. overnight. The solids were filtered and airdried to give 1.53 g of tri(indol-5-yl)bismuthine.

STEP 19B17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(indol-5-yl)bismuthine (1.3 g., 2.33 mmol.),prepared by procedures outlined in STEP 14B in CH₂ Cl₂ (30 mL.) wasadded peracetic acid (0.50 mL., 2.31 mmol., 32% in acetic acid) followedin 10 minutes by17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (1.0 g., 1.26 mmol.) and Cu(OAc)₂(100 mg., 0.55 mmol.). The reaction mixture was allowed to stir at roomtemperature for 3 days. The reaction was quenched with saturated aqueousNaHCO₃ and the mixture extracted 2× with CH₂ Cl₂. The extracts werecombined, dried with Na₂ SO₄, filtered and concentrated in vacuo. Theproduct was isolated and purified by preparative TLC 2× with 2:1hexane/acetone and once with 2:1 hexane/EtOAc to give 208 mg of thetitle compound. MASS (FAB), M+906. Partial ¹ H NMR (CDCl₃, 200 MHz)δ:8.12 (bs, 1H); 7.26 (d, J=10 Hz, 1H); 7.22 (d, J=2.5 Hz, 1H); 7.18 (m,1H); 6.9 (dd, J=2.5 Hz and 10 Hz, 1H); 6.44 (m, 1H); 3.53 (s, 3H).

EXAMPLE 2017-Allyl-1,14-dihydroxy-12-[2'-(4"-(indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(indol-5-yl)bismuthine (150 mg., 0.27 mmol.)in CH₂ Cl₂ (3 mL.) was added peracetic acid (0.05 mL., 0.23 mmol., 32%in acetic acid) followed in 15 minutes by17-allyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.124 mmol.) and Cu(OAc)₂(20 mg., 0.11 mmol.). The reaction mixture was allowed to stir at roomtemperature for 2 days. The reaction was quenched with saturated aqueousNaHCO₃ and the mixture extracted with CH₂ Cl₂. The extracts werecombined, dried with Na₂ SO₄, filtered and concentrated in vacuo. Theproduct was isolated and purified by preparative TLC 2× (2:1hexane/acetone then 5% CH₃ OH in CH₂ Cl₂) to give 11 mg of the titlecompound. MASS (FAB), M+Li 925. Partial ¹ H NMR (CDCl₃, 200 MHz) δ:8.12(bs, 1H); 7.24 (d, J=10 Hz, 1H); 7.22 (d, J=2.5 Hz, 1H); 7.17 (t, J=3Hz, 1H); 6.9 (dd, J=3 Hz and 10 Hz, 1H); 6.44 (bs, 1H); 5.70 (m, 1H);3.53 (s, 3H).

EXAMPLE 2117-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-ethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-ethylindol-5-yl)bismuthine (150 mg., 0.23mmol.), prepared by procedures outlined in STEP 14A & B, in CH₂ Cl₂ (3ml) was added peracetic acid (0.063 mL., 0.3 mmol., 32% in acetic acid)followed in 15 minutes by17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.126 mmol.) and Cu(OAc)₂(20 mg., 0.11 mmol.). The reaction mixture was allowed to stir at roomtemperature for 3 days. The reaction was then quenched with saturatedaqueous NaHCO₃ and the mixture extracted 2× with CH₂ Cl₂. The extractswere combined, dried with Na₂ SO₄, filtered, and concentrated in vacuoto a brown oil. The product was isolated and purified by preparative TLCon silica gel (first with 2:1 hexane/acetone followed by 3% CH₃ OH inCH₂ Cl₂) to give 60 mg of the title compound. MASS (FAB) M+Na 957.Partial ¹ H NMR (CDCl₃, 200 MHz) δ:7.19 (d, J=10 Hz, 1H); 7.18 (d, J=3Hz, 1H); 7.05 (d, J=4 Hz, 1H); 6.90 (dd, J=3 Hz, 10 Hz, 1H); 6.35 (d,J=4 Hz, 1H); 4.09 (q, J=6.7 Hz, 2H); 3.5 (s, 3H); 1.4 (t, J=6.7 Hz, 3H).

EXAMPLE 2217-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-ethylindol-5-yl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of tri(1-ethylindol-5-yl)bismuthine (0.2 gm) prepared byprocedures outlined in Step 14A & B in CH₂ Cl₂ (2 ml) at roomtemperature was added peracetic acid (37 μL, 0.2 mmol). After stirringfor 15 minutes at room temperature, was added17-ethyl-1,14-dihydroxy-12-[2'-(4",3"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,28-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (0.2 gm, 0.25 mmol) followed byCu(OAc)₂ (20 mg) and the reaction mixture was stirred for 2 days. To thereaction mixture was then added saturated NaHCO₃ (approximately 20 ml)and the mixture was extracted twice with CH₂ Cl₂. The combined organicextracts were dried over Na₂ SO₄, filtered and concentrated in vacuo.The mixture of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-ethylindol-5-yl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone and17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(1-ethyl-indol-5-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone were separated by chromatography(silica, 3:1, hexanes:ethyl acetate) to give the title compound (0.035gm). TLC (silica, 3:1, hexanes:ethyl acetate) R_(f) =0.55. Partial ¹ HNMR (CDCl₃, 200 MHz) δ:7.21 (d, J=10 Hz, 1H); 7.14 (d, J=3 Hz, 1H); 7.08(d, J=4 Hz, 1H); 6.85 (dd, J=3 Hz and 10 Hz, 1H); 6.36 (d, J=4 Hz, 1H),4.10 (q, J=6.7 Hz, 2H); 1.42 (t, J=6.7 Hz, 3H).

EXAMPLE 2317-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-propylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-propylindol-5-yl)bismuthine (200 mg.,0.29 mmol.), prepared by procedures analogous to STEP 14A and B, in CH₂Cl₂ (3 mL.) was added peracetic acid (0.075 mL., 0.36 mmol., 32% inacetic acid) followed in 10 minutes by17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (150 mg., 0.19 mmol.) and Cu(OAc)₂(30 mg., 0.17 mmol.). The reaction mixture was stirred for 20 hours atroom temperature. The reaction was then quenched with saturated aqueousNaHCO₃ and the mixture extracted with CH₂ Cl₂. The extracts werecombined, dried with Na₂ SO₄, filtered and concentrated in vacuo. Theproduct was isolated and purified by preparative TLC 3× on silica gel(2:1, hexane/acetone; 3% CH₃ OH in CH₂ Cl₂ ; 2:1, hexane/acetone) togive 70 mg of the title compound. MASS (FAB) M+Na 971. Partial ¹ H NMR(CDCl₃, 200 MHz) δ:7.17 (d, J=10 Hz, 1H); 7.02 (d, J=4 Hz, 1H); 6.88(dd, J=3 Hz and 10 Hz, 1H); 6.32 (d, J=4 Hz, 1H); 3.97 (t, J=7 Hz, 2H),3.50 (s, 3H); 1.80 (m, 2H).

EXAMPLE 2417-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-propylindol-5-yl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-propylindol-5-yl)bismuthine (200 mg.,0.29 mmol.), prepared by procedures analogous to Step 14A and B, in CH₂Cl₂ (3 mL.) is added peracetic acid (0.075 mL., 0.36 mmol., 32% inacetic acid) followed in 10 minutes by17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxy-3"-cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (150 mg., 0.19 mmol.) and Cu(OAc)₂(30 mg., 0.17 mmol.). The reaction mixture is stirred for 20 hours atroom temperature. The reaction is then quenched with saturated aqueousNaHCO₃ and the mixture extracted with CH₂ Cl₂. The extracts arecombined, dried with Na₂ SO₄, filtered and concentrated in vacuo. Theproduct is isolated and purified from the C-3" ether by preparative TLCon silica gel to give the title compound.

EXAMPLE 2517-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-hydroxyethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone STEP 25A1-(2-Hydroxyethyl)-5-bromoindole

A mixture of NaOH (4.4 gm, 0.011 mol) in DMSO (175 ml) was stirred at100° C. for 5 hours at which time it was cooled to 20° C. To thismixture was added 5-bromoindole (20 gm, 0.102 mol) and the reaction wasstirred for 8 hours at room temperature. A solution of ethylene oxide(5.1 gm, 0.125 mol) in DMSO (20 ml) was prepared by bubbling the gasinto DMSO. To the bromoindole reaction mixture was slowly added theethylene oxide solution and stirring was continued for another 2.5hours. The reaction mixture was then poured into ice water and extractedtwice with diethyl ether. The combined ether extracts were concentratedin vacuo whereupon crystallization took place. The crude product wasrecrystallized from diethyl ether:hexanes (3:2) to afford the titlecompound (6.25 gm).

STEP 25B 1-(2-t-Butyldimethylsilyloxyethyl)-5-bromoindole

A solution of 1(2-hydroxyethyl)-5-bromoindole (6 gm, 0.025 mol),t-butyldimethylsilyl chloride (4.5 gm, 0.03 mol) and triethylamine (4.2ml, 0.03 mol) in CH₂ Cl₂ (60 ml) was stirred for 12 hours at roomtemperature. The reaction mixture was then washed twice with H₂ O, driedover Na₂ SO₄, filtered and concentrated in vacuo to provide the titlecompound as a yellow oil. ¹ H NMR was consistent with the desiredstructure.

STEP 25C Tri[1-(2-t-butyldimethylsilyloxyethyl)-indol-5-yl]-bismuthine

To a solution of 1(2-t-butyldimethylsilyloxyethyl)-5-bromoindole (1.4gm, 0.004 mol) in diethyl ether (14 ml) at -78° C. was added t-butyllithium (4.7 ml of a 1.7M solution in pentanes, 0.008 mol). Afterstirring for 1.5 hours, a solution of bismuth trichloride (0.4 gm, 0.013mol) in THF (4 mL) was added. The reaction was stirred at -78° C. for 2hours and then allowed to warm slowly to room temperature and stirringwas continued a further 8 hours. The reaction mixture was then pouredinto H₂ O and extracted with toluene. The combined organic extracts weredried over Na₂ SO₄, filtered and the filtrate was concentrated in vacuo.Purification by chromatography (silica, 4:1, hexanes:ethyl acetate)provided the title compound (1.03 gm) as a semisolid. ¹ H NMR wasconsistent with desired structure.

STEP 25D17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-t-butyldimethylsilyloxyethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution oftri[1-(2-t-butyldimethylsilyloxyethyl)-indol-5-yl]bismuthine (1.03 gm,0.001 mol) in CH₂ Cl₂ (10 ml) at room temperature was added peraceticacid (150 μL). After stirring for 15 minutes,17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (1 gm) was added to the reactionmixture followed by Cu(OAc)₂ (0.04 gm) and the reaction mixture wasstirred for 20 hours. To the reaction mixture was then added saturatedNaHCO₃ and it was then extracted with CH₂ Cl₂. The organic extracts weredried over Na₂ SO₄, filtered and the filtrate was concentrated in vacuo.The crude product was purified by chromatography (silica, 3:1,hexanes:ethyl acetate) to provide the title compound (0.38 gm). ¹ H NMRwas consistent with desired structure.

STEP 25E17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-hydroxyethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-t-butyldimethylsilyloxyethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (0.38 gm) in CH₂ Cl₂ (10 ml) at roomtemperature was added a solution of para-toluene sulfonic acid (0.05 gm)in CH₃ OH (10 ml). The reaction mixture was stirred for 3 hours untilTLC (silica, 2:1, hexanes:ethyl acetate) verified that reaction wascomplete. The reaction mixture was poured into saturated NaHCO₃ andextracted twice with CH₂ Cl₂. The combined organic extracts were driedover Na₂ SO₄, filtered and concentrated in vacuo. The crude product waspurified by chromatography (silica, 2:1 hexanes:ethyl acetate) toprovide the title compound 0.245 gm. MASS (FAB)

M+Li 957. Partial ¹ H NMR (CDCl₃, 200 MHz) δ: 7.18 (d, J=10 Hz, 1H);7.16 (bs, 1H); 7.06 (d, J=4 Hz, 1H); 6.86 (dd, J=3 Hz and 10 Hz, 1H);6.33 (d, J=4 Hz, 1H); 4.13 (t, J=6.7 Hz, 2H); 3.83 (t, J=6.7 Hz, 2H);3.43 (s, 3H).

EXAMPLE 2617-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'-allylindol-5'-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone STEP 26A 1-Allyl-5-bromoindole

To a stirred mixture of NaOH (204 mg., 5.1 mmol., 1 eq.) in DMSO (10mL.) was added 5-bromoindole (1.0 g., 5.1 mmol., 1 eq.). The solutionwas stirred for three hours upon complete dissolution of the NaOH(approximately 1 h.). To this solution was added allyl iodide (0.466mL., 5.1 mmol., 1 eq.) via syringe. After 2 h. the mixture was dilutedwith water and extracted 2× with diethyl ether. The organic extractswere combined, dried over anhydrous MgSO₄, filtered and concentrated invacuo. The product was purified by flash column chromatography on silicagel (4:1 hexanes/acetone) affording 730 mg 1-allyl-5-bromoindole.

STEP 26B Tri(1-allylindol-5-yl)bismuthine

To a stirred solution of 1-allyl-5-bromoindole (730 mg., 3.09 mmol., 1eq.) in diethyl ether (15 mL) at -78° C. under N₂ was addedt-butyllithium (1.8 mL., 3.09 mmol., 1 eq., 1.7M solution in pentane).The mixture was stirred at -78° C. under N₂ for 1 h. To this mixture wasadded a solution of bismuth trichloride (292 mg., 0.93 mmol., 0.3 eq.)in dry THF (3 mL.) dropwise via syringe. The ice bath was packed withdry ice and the flask covered. The mixture was allowed to warm slowly toroom temperature overnight. The reaction mixture was then diluted withtoluene and washed with brine. The layers were separated and the aqueouslayer extracted 3× with toluene. The organic extracts were combined,dried over anhydrous Na₂ SO₄, filtered and concentrated in vacuo. Theresidue was dissolved in ether and filtered through a 0.4 micron pTFEmembrane. The product started to crystallize. Cooled solution infreezer. Collected crystals giving 200 mg. oftris-1-allylindol-5-yl)bismuthine.

STEP 26C17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'-allylindol-5'-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-allylindol-5-yl)bismuthine (186 mg.,0.275 mmol., 1.2 eq.) in CH₂ Cl₂ (3 mL.) was added peracetic acid (0.064mL., 0.303 mmol., 1.32 eq., 32% solution in dilute acetic acid). To thissolution was added THF (1 mL.),17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,-21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (181 mg., 0.229 mmol., 1 eq.) andcopper(II)acetate (10 mg., 0.055 mmol., 0.24 eq.). The mixture wascapped and stirred overnight. The reaction was diluted with saturatedaqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organic extracts werecombined, dried over anhydrous Na₂ SO₄, filtered and concentrated invacuo. The product was isolated and purified by flash columnchromatography on silica gel (2:1 hexanes/acetone) followed bypreparative TLC (3.5% methanol/CH₂ Cl₂) affording 56 mg pure titlecompound. MASS (FAB) M+Li 953. Partial ¹ H NMR (CDCl₃, 200 MHz) δ:7.17(bs, 1H); 7.15 (d, J=10 Hz, 1H); 7.02 (d, J=3 Hz, 1H); 6.88 (dd, J=2 Hzand 10 Hz, 1H); 6.36 (d, J=3 Hz, 1H); 5.95 (m, 1H); 4.63 (bd, J=14 Hz,1H); 3.50 (s, 3H).

EXAMPLE 2717-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'-allylindol-5'yl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-allylindol-5-yl)bismuthine (1.0 g, 1.48mmol, 1.2 eq) in CH₂ Cl₂ (9 mL) and THF (3 mL) was added peracetic acid(0.315 mL, 1.62 mmol, 1.32 eq, 32% solution in diluted acetic acid). Tothis solution was added17-ethyl-1,14-dihydroxy-12-[2'-4(4",3"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (956 mg, 1.23 mmol, 1 eq) and copper(II)acetate (22 mg, 0.123 mmol, 0.1 eq). The mixture was capped andstirred for four days. The reaction was diluted with saturated aqueousNaHCO₃ and extracted 4× with CH₂ Cl₂. The organic extracts werecombined, dried over anhydrous NaSO₄, filtered and concentrated invacuo. The product was isolated and purified by flash columnchromatography on silica gel (3:1 hexanes/acetone) followed bypreparative TLC (3.5% methanol/CH₂ Cl₂) affording 163 mg pure17-ethyl-1,14-dihydroxy-12-[2'-(4"-1'-allylindol-5'yl)oxy-3"-hydroxycyclohexyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetrone.

MASS (FAB), M+Li 953. Partial ¹ H NMR (CDCL₃, 200 MHz) δ:7.17 (d, J=10Hz, 1H); 7.15 (brs, 1H); 7.05 (d, J=3 Hz, 1H); 6.86 (dd, J=10 Hz, J=2.5Hz, 1H); 6.39 (d, J=3 Hz, 1H); 6.05-5.85 (m, 1 HO; 4.66 (brd, J=8.5 Hz,2H); 4.57 (brd, J=5 Hz, 1H); 4.38 (brd, J=13 Hz, 1H).

EXAMPLE 2817-Ethyl-1,14-dihydroxy-12-[2'-(4"-(9'-methylcarbazol-3'-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone STEP 28ATri(9-methylcarbazol-3-yl)bismuthine

To a stirred mixture of 3-bromo-9-methylcarbazole (646 mg., 2.48 mmol.,1 eq.) in diethyl ether (12 mL) at -78° C. (not all carbazole insolution) under N₂ was added t-butyllithium (3.0 mL., 4.96 mmol., 2 eq.,1.7M solution in pentane). The mixture was warmed quickly to roomtemperature and then quickly cooled to -78° C. and stirred under N₂ for40 minutes. To this mixture was added a solution of bismuth trichloride(235 mg., 0.744 mmol., 0.3 eq.) in dry THF (2.5 mL.) dropwise viasyringe. The ice bath was packed with dry ice and the flask covered. Themixture was allowed to warm slowly to room temperature overnight. Thereaction mixture was poured into a separatory funnel containing brineand extracted 4×with CH₂ Cl₂. The organic extracts were combined, driedover anhydrous Na₂ SO₄, filtered and concentrated in vacuo. The solidresidue was triturated with ether and ether/methanol. The solids werecollected giving 200 mg. of tri(9-methylcarbazol-3-yl)bismuthine. Thesupernatant was saved for further purification.

STEP 28B17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(9'-methylcarbazol-3'-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of tri(9-methylcarbazol-3-yl)bismuthine (200 mg.,0.267 mmol., 1.2 eq.) in CH₂ Cl₂ (3 mL.) and THF (1 mL.) was addedperacetic acid (0.062 mL., 0.295 mmol., 1.32 eq., 32% solution in diluteacetic acid). To this solution was added17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (175 mg., 0.222 mmol., 1 eq.) andcopper(II)acetate (10 mg., 0.055 mmol., 0.24 eq.). The mixture wascapped and stirred for 48 hours. The reaction was diluted with saturatedaqueous NaHCO₃ and extracted 4×with CH₂ Cl₂. The organic extracts werecombined, dried over anhydrous Na₂ SO₄, filtered and concentrated invacuo. The product was isolated and purified by flash columnchromatography on silica gel (3:1 hexanes/acetone) followed bypreparative TLC (3.5% methanol/CH₂ Cl₂) affording 100 mg of the titlecompound. MASS (FAB) M+Li 977. Partial ¹ H NMR (CDCl₃, 200 MHz) δ:7.68(d, J=2 Hz, 1H); 7.48-7.10 (m, 6H); 4.58 (bd, J=4.8 Hz, 1H); 4.39 (bd,J=14 Hz, 1H); 3.80 (s, 3H); 3.53 (s, 2H).

EXAMPLE 2917-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'-benzylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone STEP 29A 1-Benzyl-5-bromoindole

To a stirred mixture of NaOH (204 mg., 5.1 mmol., 1 eq.) in DMSO (10mL.) was added 5-bromoindole (1.0 g., 5.1 mmol., 1 eq.). The solutionwas stirred for 20 hours upon complete dissolution of the NaOH(approximately 1 h.). To this solution was added benzyl bromide (0.606mL., 5.1 mmol., 1 eq.) via syringe. After 7 h. the mixture was dilutedwith water and extracted 4× with diethyl ether. The organic extractswere combined, dried over anhydrous MgSO₄, filtered and concentrated invacuo. The product was purified by crystallization (ether/hexanes)affording 888 mg of 1-benzyl-5-bromoindole.

STEP 29B Tri(1-benzylindol-5-yl)bismuthine

To a stirred mixture of 1-benzyl-5-bromoindole-3 (888 mg., 3.105 mmol.,1 eq.) in diethyl ether (15 mL) at -78° C. (not all indole was insolution) under N₂ was added t-butyllithium (3.65 mL., 6.21 mmol., 2eq., 1.7M solution in pentane). The mixture was stirred at -78° C. underN₂ for 1 hour. To this mixture was added a solution of bismuthtrichloride (294 mg., 0.932 mmol., 0.3 eq.) in dry THF (3 mL.) dropwisevia syringe. The ice bath was packed with dry ice and the flask covered.The mixture was allowed to warm slowly to room temperature overnight.The reaction mixture was poured into a separatory funnel containingbrine and extracted 4× with CH₂ Cl₂. The organic extracts were combined,dried over anhydrous Na₂ SO₄, filtered and concentrated in vacuo. Thesolid residue was triurated with ether. The solids were collected giving200 mg. of tri(1-benzylindol-5-yl)bismuthine. The supernatant was savedfor further purification.

STEP 29C17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'-benzylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred mixture of tri(1-benzylindol-5-yl)-bismuthine (200 mg.,0.242 mmol., 1.2 eq.) in CH₂ Cl₂ (3 mL.) and THF (1 mL.) was addedperacetic acid (0.060 mL., .285 mmol., 1.4 eq., 32% solution in diluteacetic acid). To this solution was added17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (159 mg., 0.202 mmol., 1 eq.) andcopper(II)acetate (10 mg., 0.055 mmol., 0.24 eq.). The mixture wascapped and stirred overnight. The reaction was diluted with saturatedaqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organic extracts werecombined, dried over anhydrous Na₂ SO₄, filtered and concentrated invacuo. The product was isolated and purified by flash columnchromatography on silica gel (3:1 hexanes/acetone) followed bypreparative TLC (3.5% methanol/CH₂ Cl₂) affording 100 mg of the titlecompound. MASS (FAB) M+Li 1003. Partial ¹ H NMR (CDCl₃, 200 MHz) δ:7.3-7.0 (m, 8H); 6.84 (dd, J=9 Hz, 1H); 6.40 (d, 3 Hz, 1H); 5.23 (bs,2H); 4.6 (bd, J=6 Hz, 1H); 4.38 (bd, J=14 Hz, 1H); 3.50 (s, 3H).

EXAMPLE 3117-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone STEP 31A17-Ethyl-1-hydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9 ]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (300 mg) in 9 ml 33% methylenechloride in cyclohexane was added allyl trichloroacetimidate (138 mgneat) and the reaction mixture was allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (18 μl neat) was added slowly via syringeand the mixture stirred at room temperature. After 3 days the reactionwas diluted with ethyl acetate and quenched with saturated sodiumbicarbonate. The layers were separated, and the organic layer was washedwith brine then dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:4)+1% methanol) gave the title compound (230 mg; trichloroacatamidepresent). ¹ H NMR consistent with the desired structure.

STEP 31B17-Ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,-21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (115 mg) (STEP 31A) in acetonitrile(2.5 ml) was added a solution of 2% HF in aqueous acetonitrile (40 μl),and the mixture was stirred at room temperature. After 4 hours, thesolution was diluted with ethyl acetate and quenched with saturatedsodium bicarbonate. The layers were separated, and the organic layer waswashed with brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:2)) gave the title compound (42 mg). ¹ H NMR consistent with thedesired structure.

STEP 31C17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of tri(1-methylindol-5-yl)bismuthine (53 mg) in methylenechloride (700 μl) was added peracetic acid (17 μl), and the mixture wasstirred at room temperature for 15 minutes.17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,-21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (42 mg) was dissolved in methylenechloride (270 μl) and added to the reaction mixture. After 18 hours themixture was diluted with ethyl acetate and washed with saturated sodiumbicarbonate and brine then dried over magnesium sulfate. Purification ofthe concentrate by flash chromatography on silica gel (ethylacetate:hexane (1:3)+1% methanol) gave the title compound (25 mg). MASS(FAB) 938 (M+Li); Partial ¹ H NMR δ: 7.19 (s, 1H); 7.18 (d, J=9 Hz, 1H);6.98 (d, J=3 Hz, 1 H); 6.92 (dd, J=9,3 Hz, 1H); 6.34 (d, J=3 Hz, 1H);5.89 (m,1H); 4.56 (brd, J=4 Hz, 1H); 3.72 (s, 3H).

EXAMPLE 3217-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-n-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (20 mg) (EXAMPLE 31) in ethyl acetate(500 μl) was added rhodium on carbon (5 mg). The flask was filled withhydrogen, and the mixture was stirred at room temperature. After 1.5hours the mixture was filtered through Celite then the solvent wasremoved in vacuo to give the title compound (20 mg). MASS (FAB) 940(M+Li); Partial ¹ H NMR δ: 7.18 (s,1H); 7.16 (d, J=9 Hz, 1H); 6.96 (d,J=3 Hz, 1H); 6.92 (dd, J=9,3 Hz, 1H); 6.34 (d, J=3 Hz, 1H); 4.55 (brd,J=4 Hz, 1H); 3.72 (s, 3 H).

EXAMPLE 3317-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-i-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone STEP 33A17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-i-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (300 mg in 4.5 ml 33% methylenechloride in cyclohexane) isopropyl trichloroacetimidate (142 mg neat)was added and the reagents allowed to mix for 5 minutes.Trifluoromethanesulfonic acid (13.4 μl neat) was added slowly viasyringe and the mixture stirred at room temperature. After 5 days thereaction was diluted with ethyl acetate and quenched with saturatedsodium bicarbonate. The layers were separated, and the organic layer waswashed with brine then dried over magnesium sulfate. Purification of theconcentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compound (42 mg). ¹ H NMR consistentwith the desired structure.

STEP 33B17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-i-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of tri(1-methylindol-5-yl)bismuthine (52 mg) in methylenechloride (700 μl) was added peracetic acid (17 μl), and the mixture wasstirred at room temperature for 15 minutes.17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-i-propyloxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (42 mg) was dissolved in methylenechloride (450 μl) and added to the reaction mixture. After 18 hours themixture was diluted with ethyl acetate and washed with saturated sodiumbicarbonate and brine then dried over magnesium sulfate. Purification ofthe concentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:1+1% methanol) gave the title compound (9 mg). MASS (FAB) 956 (M+Li)Partial ¹ H NMR δ: 7.19 (s, 1H); 7.16 (d, J=9 Hz, 1H); 6.97 (d, J=3 Hz,1H); 6.92 (dd, J=9, 3 Hz, 1H); 6.34 (d, J=3 Hz, 1H); 4.41 (brd, J=14 Hz,1H); 2.72 (s, 3H).

EXAMPLE 3417-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone STEP 34A17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (1.0 g) in dry methylene chloride (14ml) was added 2,6-lutidine (240 μl) and the mixture was stirred at roomtemperature. After 10 minutes, tert-butyldimethylsilyltrifluoromethanesulfonate (295 μl) was added via syringe. After 15minutes the reaction mixture was diluted with ethyl acetate, washed with1N HCl, water, saturated sodium bicarbonate and brine. The organic phasewas dried over magnesium sulfate. Removal of the solvent in vacuo andflash chromatography on silica gel (ethyl acetate:hexane (1:3)+1%methanol) gave the title compound (293 mg). ¹ H NMR consistent with thedesired structure.

STEP 34B17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone(290 mg in 3.9 ml 33% methylene chloride in cyclohexane) allyltrichloroacetimidate (131 mg neat) was added and the reagents allowed tomix for 5 minutes. Trifluoromethanesulfonic acid (6 μl neat) was addedslowly via syringe and the mixture stirred at room temperature. After 5days the reaction was diluted with ethyl acetate and quenched withsaturated sodium bicarbonate. The layers were separated, and the organiclayer was washed with brine then dried over magnesium sulfate.Purification of the concentrate by preparative TLC on silica gel (ethylacetate:hexane (1:5)+1% methanol) gave the title compound (150 mg). ¹ HNMR consistent with the desired structure.

STEP 34C17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,-19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (150 mg) in acetonitrile (3 ml) wasadded a solution of 2% HF in aqueous acetonitrile (80 μl), and themixture was stirred at room temperature. After 2 hours, the solution wasdiluted with ethyl acetate and quenched with saturated sodiumbicarbonate. The layers were separated, and the organic layer was washedwith brine and dried over magnesium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane(1:1)+1% methanol) gave the title compound (63 mg). ¹ H NMR consistentwith the desired structure.

STEP 34D17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of tri(1-methylindol-5-yl)bismuthine (60 mg) in methylenechloride (1.0 ml) was added peracetic acid (23 μl), and the mixture wasstirred at room temperature for 15 minutes.17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (60 mg) was dissolved in methylenechloride (500 μl) and added to the reaction mixture. After 10 hours themixture was diluted with ethyl acetate and washed with saturated sodiumbicarbonate and brine then dried over magnesium sulfate. Purification ofthe concentrate by preparative TLC on silica gel (ethyl acetate:hexane(1:2)+1% methanol) gave the title compound (26 mg). partial ¹ H NMRδ:7.18 (s, 1H); 7.16 (d, J=9 Hz, 1H); 6.97 (d, J=3 Hz, 1H); 6.91 (dd,J=9, 3 Hz, 1H); 6.34 (d, J=3 Hz, 1H); 5.89 (m, 1H); 4.57 (brd, J=4 Hz,1H); 4.41 (brd, J=14 Hz, 1H); 3.70 (s, 3H).

EXAMPLE 3517-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-n-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (14 mg) in ethyl acetate (400 μl) wasadded rhodium on carbon (4 mg). The flask was filled with hydrogen, andthe mixture was stirred at room temperature. After 1.5 hours the mixturewas filtered through Celite then the solvent was removed in vacuo.Purification by flash chromatography (ethyl acetate:hexane (1:1)+1%methanol) gave the title compound (10 mg). partial 1H NMR d: 7.17 (s,1H); 7.15 (d, J=9 Hz, 1H); 6.97 (d, J=3 Hz, 1H); 6.92 (dd, J=9, 3 Hz,1H); 6.34 (d, J=3 Hz, 1H); 4.56 (brd, J=4 Hz, 1H); 4.40 (brd, J= 14 Hz,1H); 3.71 (s, 3H).

EXAMPLE 3617-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-(3-t-butyldimethylsilyloxypropyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of tri[1-(3-t-butyldimethylsilyloxypropyl)-indol-5-yl]bismuthine (0.43 gm, 0.4 mmol.) in CH₂ Cl₂ (4 mL.) at room temperaturewas added peracetic acid (0.075 mL., 32% in acetc acid) followed in 15minutes by17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (350 mg., 0.44 mmol.) and Cu(OAc)₂(30 mg.). The reaction mixture was stirred for 2 days. The reaction wasthen quenched with saturated NaHCO₃ and the mixture extracted with CH₂Cl₂. The organic extracts were combined, dried over Na₂ SO4, filtered,and concentrated in vacuo. The product was isolated and purified bypreparative TLC on silica gel (3:1, hexane/acetone) to give 144 mg. ofthe title compound.

EXAMPLE 3717-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-(3-hydroxypropyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-(3-t-butyldimethylsilyloxy-propyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (144 mg) in CH₂ Cl₂ (4 mL.) at rt wasadded a solution of p-toluene sulfonic acid (20 mg.) in CH₃ OH (4 mL.).The reaction mixture was stirred for 3 hr., quenched with saturatedNaHCO₃, then extracted with CH₂ Cl₂. The extracts were combined, driedover Na₂ SO₄, filtered and concentrated in vacuo. The product waspurified by preparative TLC on silica gel (2:1, hexane/acetone) to give81 mg of the title compound. Partial ¹ H NMR (CDCl₃, 200 MHz) d: 7.22(d, J=9 Hz, 1H); 7.18 (d, J=3 Hz, 1H); 7.07 (d, J=3 Hz, 1H); 6.89 (dd,J=3 Hz and J=9 Hz, 1H); 6.34 (d, J=3 Hz, 1H); 4.20 (t, J=6.5 Hz, 2H);2.00 (m, 2H).

EXAMPLE 3817-Ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-(1-t-butyldimethylsilyloxyethylindol-5-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of tri[1-(2-t-butyldimethylsilyloxyethyl)-indol-5-yl]bismuthine (250 mg., 0.24 mmol.) in CH₂ Cl₂ (2 mL.) at rt was addedperacetic acid (0.05 mL., 32% in acetic acid) followed in 15 minutes by17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg, 0.25 mmol) and Cu(OAc)₂ (20mg.). The reaction mixture was stirred for 2 days. The reaction was thenquenched with saturated NaHCO₃ and extracted with CH₂ Cl₂. The organicextracts were combined, dried with Na₂ SO₄, filtered and concentrated invacuo. The product was isolated and purified by preparative TLC (3:1,hexane/acetone) to afford 74 mg. of the title compound.

EXAMPLE 3917-Ethyl-1,14-dihydroxy-12-[2'-(3"hydroxy-4"-(1-hydroxyethylindol-5-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-(1-t-butyl-dimethylsilyloxyethylindol-5-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (74 mg) in CH₂ Cl₂ (2 mL.) at rt wasadded a solution of p-toluene sulfonic acid (10 mg.) in CH₃ OH (2 mL.).The reaction mixture was stirred for 3 hr., quenched with saturatedNaHCO₃, then extracted with CH₂ Cl₂. The extracts were combined, driedover Na₂ SO₄, filtered and concentrated in vacuo. The product waspurified by preparative TLC on silica gel (2:1, hexane/acetone) to give44.8 mg of the title compound. Partial ¹ H NMR (CDCl, 200 MHz) d: 7.24(d, J=9 Hz, 1H); 7.15 (d, J=3 Hz, 1H); 7.12 (d, J=3.5 Hz, 1H); 6.86 (dd,J= 3 and J=9 Hz, 1H); 6.39 (d, J=3.5, 1H); 4.20 (t, J=5, 2H).

EXAMPLE 40 Tri[1-2(t-butyldimethylsilyloxyethyl)-indol6-yl]-bismuthine

Step A: 6-Bromoindole

To a solution of 4-bromo-2-nitrotoluene (4.3 g., 20 mmol.) in DMF (40mL.) was added DMF dimethylacetal (7.15 g., 60 mmol.) and pyrrolidine(1.4 g., 20 mmol.). The solution was heated to 110° C. for 4 hr. thencooled to rt. and diluted with ethyl ether. The mixture was washed 3×with water, dried with Na₂ SO₄, filtered and the solvent evaporated. Theresidue was dissolved in 80% aqueous acetic acid (125 mL.) and heated to75° C. Zinc dust (9.75 g., 150 mmol.) was added gradually over 20 min.The reaction mixture was heated to 85° C. for 2 hr. then cooled to ˜35°C. and filtered to remove unreacted zinc. The filtrate was diluted withethyl ether, washed 3× with water then with saturated aqueous NaHCO₃.The solution was dried with Na₂ SO₄, filtered and concentrated in vacuoto ˜30 mL. then diluted with hexanes and filtered. The filtrate wasconcentrated to an off-white solid which was dissolved in hexane,filtered, and concentrated to give 1.65 g. of the title compound as alight green solid.

Step B: 1-(2-t-Butyldimethylsilyloxyethyl)-6-bromoindole

To a slurry of NaH (192 mg., 4.8 mmol., 60% oil dispersion) in DMF (4mL.) was added, dropwise, a solution of 6-bromoindole (0.85 g., 4.34mmol.) in DMF (4 mL.). After stirring for 10 min. at rt.,2-t-butyldimethylsiloxyethyl bromide ((1.15 g., 4.8 mmol., neat) wasadded and the mixture stirred for 1.5 hr. The reaction mixture waspartitioned between ice water and hexane. The organics were washed 2×with water, dried with Na₂ SO₄, filtered and concentrated in vacuo to adark oil. The product was isolated by flash column chromatography(silica, 4:1 hexanes/acetone) to give 1.04 g. of the title compound asan oil.

Step C: Tri[1-(2-t-butyldimethylsilyloxyethyl)indol-6-yl]-bismuthine

To a solution of 1-(2-t-butyldimethylsilyloxyethyl)-6-bromoindole (1.0g., 2.81 mmol.) in ethyl ether (10 mL.) at -78° C. was addedt-butyllithium (3.4 mL., 5.8 mmol., 1.7M in pentane). After stirring for10 min. a solution of BiCl₃ (285 mg., 0.9 mmol.) in THF (3 mL.) wasadded. The reaction mixture was stirred for an additional 10 min. at-78° C. then allowed to warm to rt overnight. The reaction mixture waspartitioned between ice water and CH₂ Cl₂. The organic layer was washedwith water, dried with Na₂ SO₄ and concentrated to a dark oil. Flashcolumn chromatography (silica, 4:1 hexane/acetone) afforded 630 mg. ofthe title compound as an dark oil (˜60% pure) which was used withoutfurther purification in Example 41/the next step.

EXAMPLE 4117-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-t-butyldimethylsilyloxyethylindol-6-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution oftri[1-(2-t-butyldimethylsilyloxyethyl)-indol-6-yl]bismuthine (0.60 g.,0.58 mmol.) in CH₂ Cl₂ (5 mL.) at room temperature was added peraceticacid (0.080 mL., 32% in acetic acid) followed in 15 minutes by17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (350 mg., 0.44 mmol.) and Cu(OAc)₂(30 mg.). The reaction mixture was stirred for 20 hr. The reaction wasthen quenched with saturated NaHCO₃ and the mixture extracted with CH₂Cl₂. The organic extracts were combined, dried over Na₂ SO4, filtered,and concentrated in vacuo. The product was isolated and purified bypreparative TLC on silica gel (3:1, hexane/acetone) to give 150 mg. ofthe title compound.

EXAMPLE 4217-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-hydroxyethylindol-6-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-t-butyldimethylsilyloxyethylindol-6-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (150 mg) in CH₂ Cl₂ (4 mL.) at rt wasadded a solution of p-toluene sulfonic acid (20 mg.) in CH₃ OH (4 mL.).The reaction mixture was stirred for 2 hr., quenched with saturatedNaHCO₃, then extracted with CH₂ Cl₂. The extracts were combined, driedover Na₂ SO₄, filtered and concentrated in vacuo. The product waspurified by preparative TLC on silica gel (2:1, hexane/acetone) to give55 mg of the title compound.

Partial ¹ H NMR (CDCl, 200 MHz) d: 7.47 (d, J=6 Hz, 1H); 7.03 (d, J=3Hz, 1H); 6.94 (bs, 1H); 6.82 (dd, J=1.5 Hz and J=6 Hz, 1H); 6.41 (d,J=3Hz, 1H); 6.41 (d, J=3 Hz, 1H); 4.20 (t, J=5 Hz, 2H); 3.93 (t, J=5 Hz,2H); 3.50 (s, 3H).

EXAMPLE 43 Tri(1-methylindol-6-yl)bismuthine

To a solution of 1-methyl-6-bromoindole (760 mg., 3.6 mmol.) in ethylether (15 mL.) at -78° C. was added t-butyllithium (4.4 mL., 7.5 mmol.,1.7M in pentane). After 10 min. a solution of BiCl₃ (375 mg., 1.2 mmol.)in THF (4 mL.) was added and the cooling bath removed. The reactionmixture stirred for 4 hr then poured into ice water and extracted withCH₂ Cl₂. The extracts were combined, backwashed with water, dried withNa₂ SO₄, filtered, and concentrated in vacuo to a dark oil. The productwas crystallized from methanol to afford 290 mg. of the title compoundas a tan solid.

EXAMPLE 4417-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methylindol-6-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of tri[1-methylindol-6-yl]-bismuthine (200 mg., 0.33mmol.) in CH₂ Cl₂ (2 mL.) at room temperature was added peracetic acid(0.070 mL., 32% in acetic acid) followed in 15 minutes by17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (150 mg., 0.19 mmol.) and Cu(OAc)₂(30 mg.). The reaction mixture was stirred for 4 days. The reaction wasthen quenched with saturated NaHCO₃ and the mixture extracted with CH₂Cl₂. The organic extracts were combined, dried over Na₂ SO4, filtered,and concentrated in vacuo. The product was isolated and purified bypreparative TLC on silica gel (2:1, hexane/acetone) to give 76 mg. ofthe title compound. Partial ¹ H NMR (CDCl, 400 MHz) d: 7.44 (d, J=7 Hz,1H); 6.91 (d, J=3 Hz, 1H) 6.88 (d, J=2 Hz, 1H); 6.81 (m, 1H); 6.37 (d,J=3, 1H); 3.68 (s, 3H); 3.51 (s, 3H).

EXAMPLE 4517-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-dibenzylphosphonoxy-ethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-hydroxyethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (202 mg, azeotroped with toluene) indry THF was added dibenzyl phosphate (88.6 mg) followed bytriphenylphosphine (83.5 mg). The reaction mixture was cooled down to 0°C., then added diethyl azodicarboxylate (50 mL). The reaction mixturewas stirred at 0° C. for 5 minutes, removed the ice bath, and stirred atroom temperature for 2 h. The crude reaction mixture was loaded directlyonto the silica gel column and purified (ethyl acetate:hexane (2:3)+1%MeOH) to give the title compound (197 mg).

Partial ¹ H NMR (CDCl₃)d: 7.29 (m, 6H); 7.18 (m, 5H); 7.12 (d, J=9Hz,1H); 7.0 (d, J=4Hz, 1H); 6.89 (dd, J=9, 2Hz, 1H); 6.36 (d, J=4 Hz, 1H);4.82 (m, 4H); 4.40 (brd, J=14 Hz, 1H); 4.20 (m, 4H).

EXAMPLE 46 Monopotassium salt of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-phosphonoxy-ethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,-21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-dibenzylphosphate-ethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (197 mg) in methanol (3.2 mL) wasadded potassium bicarbonate (16.3 mg) dissolved in water (200 mL). Addedpalladium hydroxide over carbon, then charged the reaction mixture withhydrogen via balloon. After the reaction was complete (10 min. by TLCanalysis), it was filtered over Celite and rinsed with methanol andsmall amount of water. The solvent was removed in vacuo, and the crudematerial was purified on HP-20 column to give the title compound (69mg).

Partial ¹ H NMR (CD₃ OD) d: 7.34 (d, J=9 Hz, 1H); 7.27 (d, J=4 Hz, 1H);7.12 (d, J=2 Hz, 1H); 6.85 (dd, J=9, 2 Hz, 1H); 6.31 (d, J=4 Hz, 1H);5.23 (m, 2H); 4.35 (m, 2H); 4.13 (m, 2H).

EXAMPLE 4717-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-(N,N-dimethylglycyloxy)ethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-hydroxyethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (26.6 mg) in dry methylene chloride(0.3 mL) was added hydrochloride salt of N,N-dimethylglycine (5.8 mg),DMAP (3.4 mg) and EDC (8 mg), respectively at room temperature. Thereaction mixture was stirred for 4 h, then diluted with ethyl acetateand washed with saturated sodium bicarbonate and brine. The organiclayer was dried over magnesium sulfate, and the solvent was removed invacuo. The crude material was purified by flash chromatography(1:2/acetone:hexane). to give 23 mg of the title compound.

Partial ¹ H NMR (CDCl₃) d: 7.21 (m, 2H); 7.04 (d, J=4 Hz, 1H); 6.91 (dd,J=9, 2 Hz, 1H); 6.49 (d, J=4 Hz, 1H); 4.41 (m, 2H); 4.32 (m, 2H); 3.07(s, 3H); 2.26 (s, 3H).

EXAMPLE 4817-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-succinyloxyethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-hydroxyethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (109 mg) in dry methylene chloridewas added succinic anyhydride (11.5 mg) and triethylamine (19 ml). AddedDMAP (7 mg) to the reaction mixture and followed the reaction by TLC.After 1.5 h, the reaction mixture was diluted with ethyl acetate andadjusted to pH 4 with 1N HCl. It was poured into the separatory funneland the layers were separated. The aqueous layer was extracted withethyl acetate, and the combined organic layer was washed with brine. Itwas dried over magnesium sulfate, and the crude material was purified byflash chromatography (3% methanol/CH₂ Cl₂) to give 66 mg of the titlecompound.

Partial ¹ H NMR (CDCl₃) d: 7.19 (m, 2H); 7.04 (d, J=4 Hz, 1H); 6.91 (dd,J=9, 2 Hz, 1H); 6.39 (d, J=4 Hz, 1H); 4.32 (m, 4H); 2.49 (brs, 4H).

EXAMPLE 4917-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methyl-3-phenylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Step A: 5-Bromo-3-phenylisatin

To a stirred mixture of 5-bromoisatin (5 g., 22.1 mmol., 1 eq.) in dryTHF (150 mL.) was added phenylmagnesium bromide (14.7 mL., 44.2 mmol., 2eq., 3M solution in diethyl ether) (The addition of Grignard reagent wasinitiated at -78° C. The reaction mixture became too viscous to stirafter addition of approximately 5 mL. of the Grignard reagent. Thecooling bath was removed and the remainder of the Grignard reagent wasadded by quick dropwise addition.). The reaction mixture was stirredovernight. Analysis by TLC showed a small amount of unreacted startingmaterial. An additional 1.5 mL. of the Grignard reagent was added andthe reaction mixture was stirred an additional 6 hours. The reactionmixture was poured into a separatory funnel containing saturated aqueousammonium chloride and was extracted 4× with diethyl ether. The organicextracts were combined, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The product was carried on without furtherpurification.

Step B: 5-Bromo-3-phenylindole

To a stirred solution of 5-bromo-3-phenylisatin (6.39 g., 21 mmol., 1eq.) in dry THF (50 ml.) at 0° C. was added lithium aluminum hydride(2.0 g., 52.5 mmol., 2.5 eq.) portionwise over 1.5 hours. The coolingbath was removed and the reaction was allowed to stir overnight. Themixture was cooled to 0° C. and carefully quenched with 1N aqueous HCl.The mixture was filtered through Celite™ and the Celite™ was washed withTHF. The filtrate was concentrated in vacuo, dissolved in EtOAc andwashed with water. The organic layer was dried over anhydrous MgSO₄,filtered and concentrated in vacuo.

Step C: 5-bromo-1-methyl-3-phenylindole

To a stirred solution of 5-bromo-3-phenylindole (2.4 g., 8.78 mmol., 1eq.) in dimethylformamide (20 mL.) was added NaH (422 mg. of a 60%dispersion in oil, 10.54 mmol., 1.2 eq.). The mixture was stirred 15minutes. Methyl iodide (0.6 ml, 9.66 mmol, 1.1 eq) was added via syringeand the reaction mixture was stirred 3 hours. The reaction was quenchedwith water and extracted 4× with EtOAc. The organic extracts werecombined, dried over anhydrous MgSO₄, filtered and concentrated invacuo.

The product was purified by flash column chromatography (2:1hexanes/acetone) giving 1.63 g. 5-bromo-1-methyl-3-phenylindole.

Step D: Tri(1-methyl-3-phenylindol-5-yl)bismuthine

To a stirred solution of 5-bromo-1-methyl-3-phenylindole (1.63 g., 5.7mmol., 1 eq.) in Et₂ O (35 mL.) at -78° C. under N₂ atmosphere was addedt-buLi (6.7 mL. of a 1.7M solution in hexanes, 11.4 mmol., 2 eq.)dropwise via syringe. The reaction was stirred 10 minutes at -78° C. Tothis mixture was added a solution of BiCl₃ (540 mg., 1.71 mmol., 0.3eq.) in THF (7 mL.) dropwise quickly. The reaction was stirred 10minutes at -78° C. and the cooling bath was removed and the mixtureallowed to warm to room temperature. After 3 hours the mixture waspoured into a separatory funnel containing water and extracted 4× withCH₂ Cl₂. The organic extracts were combined, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was triturated withEt₂ O and the solids collected and washed with Et₂ O giving 710 mg ofTri(1-methyl-3-phenylindol-5-yl)bismuthine.

Step E:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methyl-3-phenylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-methyl-3-phenylindol-5-yl)bismuthine (645mg., 0.78 mmol., 1.2 eq.) in CH₂ Cl₂ (10 mL.) and THF (3 mL.) was addedperacetic acid (0.514 mL. of a 32% solution in dilute acetic acid, 0.858mmol., 1.3 eq.). The mixture was stirred 5 minutes and17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (514 mg., 0.65 mmol., 1 eq.) wasadded. Cu(OAc)₂ (12 mg., 0.065 mmol., 0.1 eq) was added. The flask wascapped and the mixture stirred. After 48 hours the reaction was quenchedwith saturated aqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organicextracts were combined, dried over anhydrous Na₂ SO₄, filtered andconcentrated in vacuo. The product was purified by flash columnchromatography on silica gel (2:1 hexanes/acetone) and again (3.5% CH₃OH/CH₂ Cl₂) giving 78 mg17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methyl-3-phenylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone.

Mass (FAB) 1003 (M⁺ +Li); 996 (M⁺).

Partial ¹ H NMR (CDCl₃, 400 MHz) d: 7.59 (d, J=7 Hz, 2H); 7.50 (m, 1H);7.41 (t, J=7 Hz, 2H); 7.25-7.15 (m, 3H); 6.99 (dd, J=9 Hz, J=2 Hz, 1H);4.57 (d, J=6 Hz, 1H); 4.39 (bd, J=13 Hz, 1H); 3.78 (s, 3H).

EXAMPLE 5017-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methyl-3-(2-hydroxyethyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Step A: 5-Bromo-3-hydroxyethylindole

To a stirred solution of 5-bromoindole-3-acetic acid (1.9 g., 7.48mmol., 1 eq.) in dry THF (17 mL.) at 0° C. was added lithium aluminumhydride (570 mg. 14.96 mmol., 2 eq.) portionwise over 30 minutes. Thereaction mixture coagulated. THF (20 mL.) was added and the cooling bathwas removed. The mixture was stirred vigorously. Let stir overnight. Thereaction mixture was carefully quenched with 1N aqueous HCl and thenacidified with 2N aqueous HCl. The mixture was filtered through Celite™and the Celite™ was washed with THF. The filtrate was concentrated invacuo, dissolved in EtOAc, and washed with water. The organic layer wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo. TLCanalysis of the residue showed unreacted starting material. The residuewas dissolved in Et₂ O and extracted with 0.25N aqueous NaOH. Theorganic layer was dried over anhydrous MgSO₄, filtered and concentratedin vacuo giving 1.16 g 5-bromo-3-hydroxyethylindole.

Step B: 5-Bromo-3-(2-t-butyldimethylsilyloxy)ethylindole

To a stirred solution of 5-bromo-3-hydroxyethylindole (1.16 g., 4.83mmol., 1 eq.) in CH₂ Cl₂ (12 mL.) was added triethylamine (1.0 mL., 7.25mmol., 1.5 eq.) followed by addition of t-butyldimethylchlorosilane (875mg., 1.2 mmol., 1.2 eq.) and dimethylaminopyridine(catalytic). Themixture was stirred overnight, poured into a separatory funnelcontaining water and extracted 4× with CH₂ Cl₂. The organic extractswere combined, dried over anhydrous Na₂ SO₄, filtered and concentratedin vacuo giving 1.66 g.5-bromo-3-(2-t-butyldimethylsilyloxy)ethylindole.

Step C: 5-Bromo-1-methyl-3-(2-t-butyldimethylsilyloxy)ethylindole

To a stirred solution of5-bromo-3-(2-t-butyldimethylsilyloxy)ethylindole (1.66 g., 4.66 mmol., 1eq.) in DMF (15 mL.) was added NaH (225 mg. of a 60% dispersion in oil,5.6 mmol., 1.2 eq.). After 15 minutes iodomethane (0.320 mL., 5.13mmol., 1.1 eq.) was added. The mixture was stirred 4 hours and thenpoured into a separatory funnel containing water and extracted 2× withEtOAc. The organic extracts were combined, dried over anhydrous MgSO₄,filtered and concentrated in vacuo giving 1.49 g.5-bromo-1-methyl-3-(2-t-butyldimethylsilyloxy)ethylindole.

Step D:Tri(1-methyl-3-(2-t-butyldimethylsilyloxy)ethylindol-5-yl)bismuthine

To a stirred solution of5-bromo-1-methyl-3-(2-t-butyldimethylsilyloxy)ethylindole (1.49 g., 4.03mmol., 1 eq.) in Et₂ O (15 mL.) at -78° C. under nitrogen atmosphere wasadded t-butyllithium (4.8 mL.) of a 1.7M solution in pentanes, 8.06mmol., 2 eq.) dropwise via syringe. The mixture was stirred 10 minutesat -78° C. and then a solution of BiCl₃ (381 mg., 1.21 mmol., 0.3 eq.)in THF (5 mL.) was added quickly dropwise via syringe. The mixture wasstirred for 7 minutes at -78° C. under nitrogen. The cooling bath wasremoved and the mixture was allowed to warm to room temperature. After 1hour the mixture was poured into a separatory funnel containing waterand extracted 4× with CH₂ Cl₂. The organic extracts were combined, driedover anhydrous Na₂ SO₄, filtered and concentrated in vacuo giving 554mg. crude product. ¹ H NMR analysis of the residue indicates mixture ofapproximately 2:1 of the desired bismuthine to reduced indole. Used themixture crude in subsequent reaction.

Step E:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methyl-3-(2-t-butyldimethylsilyloxyethyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution oftri(1-methyl-3-(2-t-butyldimethylsilyloxy)ethylindol-5-yl)bismuthine(554 mg. crude) in CH₂ Cl₂ (10 mL.) and THF (3 mL.) was added peraceticacid (0.12 mL. of a 32% solution in dilute acetic acid, 0.571 mmol.). Tothis mixture was added17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (347 mg., 0.439 mmol.) followed byaddition of Cu(OAc)₂ (24 mg., 0.13 mmol.). The reaction mixture wasallowed to stir overnight. The mixture was poured into a separatoryfunnel containing saturated aqueous NaHCO₃ and extracted 4× with CH₂Cl₂. The organic extracts were combined, dried over anhydrous Na₂ SO₄,filtered and concentrated in vacuo. The product was purified by flashcolumn chromatography on silica gel (2:1 hexanes/acetone) giving 200 mg.17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methyl-3-(2-t-butyldimethylsilyloxyethyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3,10,16-tetraone as a brown oil.

Step F:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methyl-3-(2-hydroxyethyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methyl-3-(2-t-butyldimethylsilyloxyethyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg.) in CH₂ Cl₂ (6 mL.) and CH₃OH (6 mL.) was added p-toluenesulfonic acid monohydrate (30 mg.). Thereaction mixture was allowed to stir 3 hours. The reaction was quenchedwith saturated aqueous NaHCO₃ and extracted 4× with CH₂ Cl₂. The organicextracts were combined, dried over anhydrous Na₂ SO₄, filtered andconcentrated in vacuo. The product was purified by preparative TLC onsilica gel (1:1 hexanes/acetone) and again (7% CH₃ OH/CH₂ Cl₂) giving-(4"-(1-methyl-3-(2-hydroxyethyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone.

Mass (FAB) 972 (M⁺ +Li).

Partial ¹ H NMR (CDCl₃, 400 MHz) d: 7.17-7.13 (m, 2H); 6.94 (dd, J=9 Hz,J=2 Hz, 1H); 6.88 (s, 1H); 4.58 (d, J=6 Hz, 1H); 4.39 (bd, J=13 Hz, 1H);3.84 (t, J=6 Hz, 2H); 3.70 (s, 3H); 2.94 (t, J=7 Hz, 2H).

EXAMPLE 5117-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1,3-dimethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Step A: 5-Bromo-3-methylindole

To a stirred mixture of 5-bromoisatin (5 g., 22.1 mmol., 1 eq.) in dryTHF (150 mL.) was added methylmagnesium bromide (32 mL. of a 1.4Msolution in toluene, 44.2 mmol., 2 eq.) dropwise via syringe. After 45minutes TLC analysis showed small amount of unreacted bromoisatin. Added3.2 mL. of methylmagnesium bromide solution. Let stir 1 hour. Cooledreaction mixture to 0° C. Added lithium aluminum hydride (1.26 g., 33.15mmol., 1.5 eq.) portionwise. Let stir 30 minutes at 0° C. Removedcooling bath and let stir overnight. Cooled mixture to 0° C. andcarefully quenched reaction with 1N aqueous HCl. Acidified with 2Naqueous HCl. Removed cooling bath. Let stir for 3 hours. Filteredmixture through Celite™. Washed Celite™ with THF. Concentrated filtratein vacuo. Diluted residue with water and extracted 4× with CH₂ Cl₂. Theorganic extracts were combined, dried over anhydrous Na₂ SO₄, filteredand concentrated in vacuo. Loaded residue onto a silica gel plug in afritted filter and eluted with 4:1 hexanes/acetone. Collected fractionscontaining the desired product and concentrated in vacuo giving 2.85 g.5-bromo-3-methylindole.

Step B: 5-Bromo-1,3-dimethylindole

To a stirred solution of 5-bromo-3-methylindole (2.85 g., 13.6 mmol., 1eq.) in DMF (35 mL.) was added NaH (651 mg. of a 60% dispersion in oil,16.28 mmol., 1.2 eq.). The mixture was stirred 15 minutes. To thismixture was added iodomethane (0.930 mL., 14.93 mmol., 1.1 eq.). Themixture was stirred for 2 hours. The DMF was removed in vacuo. Theresidue was diluted with water and extracted 4× with Et₂ O. The organicextracts were combined, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo giving 3.04 g. 5-bromo-1,3-dimethylindole as areddish liquid.

Step C: Tri(1,3-dimethylindol-5-yl)bismuthine

To a stirred solution of 5-bromo-1,3-dimethylindole (3.04 g., 13.57mmol., 1 eq.) in Et₂ O (50 mL.) at -78° C. under nitrogen atmosphere wasadded t-butyllithium (16 mL. of a 1.7M solution in hexanes, 27.2 mmol.,2 eq.) dropwise via syringe. The mixture was stirred for 10 minutes at-78° C. To the reaction was added a solution of BiCl₃ (1.28 g., 4.07mmol., 0.3 eq.) in THF (17 mL.) quickly dropwise via syringe. Themixture was stirred 5 minutes at -78° C. The cooling bath was removedand the reaction was allowed to warm to room temperature. The reactionmixture was poured into a separatory funnel containing ice water andextracted 4× with CH₂ Cl₂. The organic extracts were combined, driedover anhydrous Na₂ SO₄, filtered and concentrated in vacuo. The residuewas triturated with Et₂ O. The solids were filtered off. The filtratewas concentrated in vacuo. giving 1.28 g. brown oil. ¹ H NMR analysis ofthe residue indicates material is a mixture of approximately 1:2 desiredtri(1,3-dimethylindol-5-yl)bismuthine: dimethylindole. Material was usedcrude in subsequent Step D.

Step D:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1,3-dimethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1,3-dimethylindol-5-yl)bismuthine(approximately 420 mg. [based on 1.28 g. of material containing onethird bismuthine, 0.7 mmol., 1.2 eq.) in CH₂ Cl₂ (12 mL.) and THF (4mL.) was added peracetic acid (0.193 mL. of a 32% solution in aceticacid, 0.916 mmol., 1.3 eq.). To this mixture was added17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (464 mg., 0.59 mmol., 1 eq.) followedby addition of Cu(OAc)₂ (30 mg., 0.176 mmol., 0.3 eq.). The mixture wasstirred 4 days. The reaction was quenched with saturated aqueous NaHCO₃and extracted 4× with CH₂ Cl₂. The organic extracts were combined, driedover anhydrous Na₂ SO₄, filtered and concentrated in vacuo. The productwas purified by flash column chromatography (2:1 hexanes/acetone) andagain (3.5% CH₃ OH/CH₂ Cl₂) followed by preparative TLC (eluted 6× with4:1 hexanes/acetone) giving 117 mg. of17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1,3-dimethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone.

Mass (FAB) 934 (M⁺).

Partial ¹ H NMR (CDCl₃, 400 MHz) d: 7.14-7.10 (m, 2H); 6.91 (dd, J=9 Hz,J=2 Hz, 1H); 6.76 (s, 1H); 4.57 (d, J=6 Hz, 1H); 4.39 (bd, J=13 Hz, 1H);3.66 (s, 3H); 2.24 (s, 3H).

EXAMPLE 5217-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-benzylindol-5-yl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-benzylindol-5-yl)bismuthine (1.28 g.,1.54 mmol., 1.2 eq.) in CH₂ Cl₂ (9 mL.) and THF (3 mL.) was addedperacetic acid (0.357 mL. of a 32% solution in dilute acetic acid, 1.69mmol., 1.3 eq.). To this mixture was added17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (1 g., 1.28 mmol., 1 eq.) followed byaddition of Cu(OAc)₂ (23 mg.). The mixture was stirred 2 days. Thereaction was quenched with saturated aqueous NaHCO₃ and extracted 4×with CH₂ Cl₂. The organic extracts were combined, dried over anhydrousNa₂ SO₄, filtered and concentrated in vacuo. The product was purified byflash column chromatography on silica gel (2:1 hexanes/acetone) andagain (3.5% CH₃ OH/CH₂ Cl₂) and again (2:1 hexanes/acetone) giving 253mg.17-ethyl-1,14-dihydroxy-12-[2'-(4"-(1-benzylindol-5-yl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone.

Mass (FAB) 990(M⁺ +Li)..

Partial ¹ H NMR (CDCl₃, 400 MHz): 7.30-7.05 (m, 8H); 6.82 (dd, J=2 Hz,J=8 Hz, 1H); 6.43 (d, J=3 Hz, 1H); 5.27 (s, 2H); 4.58 (d, J=6 Hz, 1H);4.40 (bd, J=13 Hz, 1H).

EXAMPLE 5317-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-(3-hydroxypropyl)indol-6-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

Step A: 2-t-Butyldimethylsilyloxyethyl bromide

To a solution of 2-bromoethanol (50 g, 0.40 mol) in CH₂ Cl₂ (50 mL) wasadded t-butyldimethylchlorosilane (63.4 g, 0.42 mol), triethylamine(45.4 g, 0.45 mol) and dimethylaminopyridine (0.5 g). After stirringovernight the reaction mixture was washed 3× with water. The organicfraction was dried with Na₂ SO₄, filtered, and concentrated in vacuo toprovide 85 g of the title compound as a light yellow oil.

¹ H NMR (CDCl₃) δ:3.85 (t, 2H); 3.36 (t, 2H); 0.86 (s, 9H); 0.05 (s,6H).

Step B: 1-(2-Butyldimethylsilyloxyethyl)-5-bromoindole

To a slurry of sodium hydride (12 g, 0.3 mol, 60% dispersion in oil) inDMF (200 mL) was added dropwise a solution of 5-bromoindole (50 g, 0.255mol) in DMF (300 mL). After stirring for 15 minutes2-t-butyldimethylsilyloxyethyl bromide (60 g, 0.255 mol, neat) was addeddropwise and the reaction mixture stirred for 1 hour. The reactionmixture was partitioned between ice water and ethyl ether. The organicfraction was washed with water, dried over Na₂ SO₄, filtered andconcentrated in vacuo. The product was purified by column chromatography(silica, 3:1 hexane/acetone) to give 68.6 g of the title compound as alight yellow oil.

¹ H NMR (CDCl₃) δ:7.72 (s, 1H); 7.1-7.3 (m, 3H); 6.4 (d, 1H); 4.18 (t,2H); 3.86 (t, 2H); 0.8 (s, 9H); 0.18 (s, 6H).

Step C:17-Ethyl-1,14-dihdroxy-12-[2'-(4"-(1-(3-t-butyldimethylsilylxpropyl)indol-6-yl)oxy-3"-methoxcyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution oftri[1-(3-t-butyldimethylsilyloxypropyl)-indol-6-yl]bismuthine (0.917 gm,crude) in CH2Cl2 (7mL) at room temperature was added peracetic acid(0.10 mL, 32% in acetic acid) followed in 15 minutes by17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (500 mg., 0.63 mmol) and Cu(OAc)₂ (50mg). The reaction mixture was stirred for 2 days. The reaction was thenquenched with saturated NaHCO₃ and the mixture extracted with CH₂ Cl₂.The organic extracts were combined, dried over Na₂ SO₄, filtered, andconcentrated in vacuo. The product was isolated and purified bypreparative TLC on silica gel (3:1,hexane/acetone) to give 318 mg of thetitle compound.

Step D:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-(3-hydroxypropyl)indol-6-yl)oxy-3"-methoxycyclohexyl)-1"-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22,3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-(3-t-butyldimethylsilyloxypropyl)indol-6-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (318 mg) in CH₂ Cl₂ (5 mL) at rt wasadded a solution of p-toluene sulfonic acid (25 mg) in CH₃ OH (5 mL).The reaction mixture was stirred for 3 hours quenched with saturatedNaHCO₃, then extracted with CH₂ Cl₂. The extracts were combined, driedover Na₂ SO₄, filtered and concentrated in vacuo. The product waspurified by preparative TLC on silica gel (2:1,hexane/acetone) to give190 mg of the title compound.

Partial 1H NMR (CDCl₃, 200 MHz) δ:7.43 (d, J=9 Hz, 1H); 7.02 (d, J=2 Hz,1H); 6.98 (d, J=3 Hz, 1H); 6.78 (dd, J=2 Hz and J=9 Hz, 1H); 6.38 (d,J=3 Hz, 1H); 4.20 (t, J=6.5 Hz, 2H); 2.00 (m, 2H).

EXAMPLE 5417-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-diethylaminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-hydroxyethyl)-indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (200 mg., 0.210 mmol., 1 eq.) in CH₂Cl₂ (2 mL.) under nitrogen was added 3-N,N-diethylaminopropionic acidhydrochloride (57 mg., 0.315 mmol., 1.5 eq.), dimethylaminopyridine (26mg., 0.210 mmol., 1 eq.) and EDC (60 mg., 0.315 mmol., 1.5 eq.). Thereaction was stirred for 1 hour. The mixture was diluted with ethylacetate, washed with 1N aq. HCl, saturated aqueous NaHCO₃ and thenbrine. The organic layer was dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The product was purified by flash columnchromatography (3:2 hexanes/acetone) to give 194 mg.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-diethylaminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1079 (M⁺ +1).

EXAMPLE 5517-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-dimethylaminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

The title compound is prepared in the manner of Example 54 employing3-N,N-dimethylaminopropionic acid.

EXAMPLE 5617-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-aminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

The title compound is prepared in the manner of Example 54 employing3-aminopropionic acid in suitably protected form followed bydeprotection of the amino group.

EXAMPLE 5717-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-benzyloxycarbonyl-2'""-benzyloxycarbonylaminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-hydroxyethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (500 mg., 0.526 mmol., 1 eq.) in CH₂Cl₂ (5 mL.) under nitrogen was added N-Cbz-aspartic acid-β-benzyl ester(225 mg., 0.631 mmol., 1.2 eq.), dimethyl-aminopyridine (64 mg., 0.526mmol., 1 eq.) and EDC (120 mg., 0.631 mmol., 1.2 eq.). The reaction wasstirred for 2 hours. TLC analysis indicated reaction complete. Themixture was diluted with ethyl acetate, washed with 1N aq. HCl,saturated aqueous NaHCO₃ and then brine. The organic layer was driedover anhydrous MgSO₄, filtered and concentrated in vacuo. The productwas purified by flash column chromatography (70:30 hexanes/acetone) togive 687 mg 17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-benzyloxycarbonyl-2'""-benzyloxycarbonylaminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone.

EXAMPLE 5817-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(aspartyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-benzyloxycarbonyl-2'""-benzyloxy-carbonylaminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (125 mg. 0.093 mmol., 1 eq.) inmethanol (2 mL.) was added palladium hydroxide on carbon (25 mg.). Theflask was charged with hydrogen and allowed to stir for 30 minutes. Thereaction was filtered through a 0.45 μm PTFE membrane and concentratedin vacuo. The product was purified by flash column chromatography(100:10:5:0.5/CHCl₃ :MeOH:formic acid:H₂ O) to give 95 mg17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(aspartyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1067 (M⁺).

EXAMPLE 5917-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(1'""-imidazolylcarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-hydroxyethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,38-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (1.5 g., 1.58 mmol., 1 eq.) in CH₂Cl₂ (15 mL.) under nitrogen was added carbonyl diimidazole (256 mg.,1.58 mmol., 1 eq.). After 45 minutes the reaction mixture was dilutedwith ethyl acetate, washed with 1N aq. HCl and then brine. The organiclayer was dried over anhydrous MgSO₄, filtered and concentrated invacuo. The residue was used without further purification.

EXAMPLE 6017-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2""-(1'""-piperazinocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(1'""-imidazolylcarbonyloxy)ethyl)-indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.096 mmol., 1 eq.) in THF(1 mL.) at room temperature under nitrogen was added piperazine (82 mg.,0.956 mmol., 10 eq.). The mixture was stirred for 2 hours at roomtemperature, stored overnight in freezer then stirred for an additional6 hours at room temperature. The reaction was diluted with ethylacetate, washed with 1N HCl, saturated NaHCO₃, and brine. The productwas purified by flash column chromatography on silica gel (5%methanol/CH₂ Cl₂ and then 5% methanol/CH₂ Cl₂ plus 1% NH₄ OH) to give 74mg. Mass (FAB) 1064 (M⁺ +1).

EXAMPLE 6117-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(2'""-hydroy)ethylaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(1'""-imidazolylcarbonyloxy)-ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.096 mmol., 1 eq.) in THF(1 mL.) at room temperature under nitrogen was added ethanolamine (29μL., 0.478 mmol., 5 eq.). The reaction was stirred for 30 minutes atroom temperature. The reaction was diluted with ethyl acetate, washedwith 1N HCl, saturated NaHCO₃, and brine. The product was purified byflash column chromatography on silica gel (45/65 acetone/hexanes) togive 50 mg.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(2'""-hydroy)ethylaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1061 (M⁺ +Na); 1038 (M⁺+1).

EXAMPLE 6217-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(isopropyaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(1'""-imidazolylcarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (116 mg., 0.111 mmol., 1 eq.) in THF(1 mL.) at room temperature under nitrogen was added isopropylamine (48μL., 0.555 mmol., 5 eq.). The reaction was stirred for overnight. Thereaction was diluted with ethyl acetate, washed with 1N HCl and brine.The product was purified by flash column chromatography on silica gel(2:3 acetone/hexanes) to give 50 mg.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(isopropyaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1043 (M⁺ +Li).

EXAMPLE 6317-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(1'""-piperidinocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(1'""-imidazolylcarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (150 mg., 0.143 mmol., 1 eq.) in THF(1 mL.) at room temperature under nitrogen was added piperidine (42 μL.,0.717 mmol., 5 eq.). The reaction was stirred 1 hour. The reaction wasdiluted with ethyl acetate, washed with 1N HCl and brine. The productwas purified by flash column chromatography on silica gel (4:1hexanes/acetone) to give 115 mg.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(1'""-piperidinocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1062 (M⁺).

EXAMPLE 6417-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(1'""-morphilinocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(1'""-imidazolylcarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.096 mmol., 1 eq.) in THF(1 mL.) at room temperature under nitrogen was added morphiline (42 μL.,0.478 mmol., 5 eq.). The reaction was stirred 4 hours. The reaction wasdiluted with ethyl acetate, washed with 1N HCl, saturated aqueous NaHCO₃and brine. The product was purified by preparative TLC on silica gel (4%MeOH/CH₂ Cl₂) to give 85 mg. product. The compound was further purifiedby preparative TLC on silica gel (4% MeOH/CH₂ Cl₂) to give 67 mg.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(1'""-morphilinocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinvyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1064 (M⁺).

EXAMPLE 6517-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(diphenylaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-hydroxyethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.105 mmol., 1 eq.) in CH₂Cl₂ (1 mL.) under nitrogen was added diphenylcarbamylchloride (29 mg.,0.13 mmol., 1.2 eq.), triethylamine (22 μL., 0.16 mmol., 1.5 eq.) anddimethylaminopyridine (3 mg., 0.021 mmol., 0.2 eq.). The reaction wasstirred overnight. More diphenylcarbamylchloride (15 mg.) andtriethylamine (11 μL.) were added. After 3 hours the reaction mixturewas diluted with ethyl acetate, washed with 1N aq. HCl, water and thenbrine. The organic layer was dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The product was purified by preparative TLC (3%MeOH/CH₂ Cl₂) to give 50 mg.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(diphenylaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1046 (M⁺).

EXAMPLE 6617-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(diethylaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-hydroxyethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg., 0.105 mmol., 1 eq.) in CH₂Cl₂ (1 mL.) under nitrogen was added diethylcarbamylchloride (16 μL.,0.13 mmol., 1.2 eq.), triethylamine (22 μL., 1.5 eq.), anddimethylaminopyridine (13 mg., 1.0 eq.). The reaction was stirredovernight. The mixture was heated and maintained at reflux for 4 days.The mixture was cooled, diluted with ethyl acetate, washed with 1N aq.HCl and then brine. The organic layer was dried over anhydrous MgSO₄,filtered and concentrated in vacuo. The product was purified bypreparative TLC (3% MeOH/CH₂ Cl₂) to give 16 mg.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(diethyaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 1057 (M⁺ +Li).

EXAMPLE 6717-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-methanesulfonyloxyethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-hydroxyethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (500 mg., 0.526 mmol., 1 eq.) in CH₂Cl₂ (20 mL.) under nitrogen at 0° C. was added triethylamine (147 μL.,1.053 mmol., 2 eq.), followed by methanesulfonylchloride (54 μL., 0.579mmol., 1.1 eq.). The reaction was stirred 10 minutes and the coolingbath was removed. The reaction was stirred at room temperature for threehours. The mixture was stored in the freezer overnight. The solvent wasremoved in vacuo. The product was used without purification

EXAMPLE 6817-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-azidoethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-methanesulfonyloxyethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (0.526 mmol., 1 eq.) in DMF (10 mL.)under nitrogen was added sodium azide (171 mg., 2.63 mmol., 5 eq.)., Thereaction was heated to 60° C. for 2 hours. The solvent was removed invacuo. The residue was diluted with ethyl acetate and washed with brine.The aqueous layer was extracted 3× with ethyl acetate. The organicextracts were dried over anhydrous MgSO₄, filtered and concentrated invacuo. The product was purified by flash column chromatography on silicagel (2:1 hexanes/acetone) giving 310 mg.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-azidoethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 975 (M⁺).

EXAMPLE 6917-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-aminoethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-azidoethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (260 mg., 0.27 mmol., 1 eq.) in THF(6 mL.) was added water (7 drops) followed by triphenylphosphine (87mg., 0.33 mmol., 1.25 eq.). The reaction was stirred at room temperaturefor 16 hours. The solvent was removed in vacuo. The product was purifiedby flash column chromatography on silica gel (10% MeOH/CH₂ Cl₂) giving227 mg.17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-aminoethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone. Mass (FAB) 956(M⁺ +Li).

EXAMPLE 7017-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-t-butyldimethylsilyloxyethoxyethylindol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution oftri[1-(2-t-butyldimethylsilyloxy-ethoxyethyl)-indol-5-yl] bismuthine(360 mg., 0.31 mmol.) in CH₂ Cl₂ (3 mL.) at rt was added peracetic acid(0.05 mL., 32% in acetic acid) followed in 10 minutes by17-Ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone (200 mg, 0.25 mmol) and Cu(OAc)₂ (20mg.). The reaction mixture was stirred for 18 hrs. The reaction was thenquenched with saturated NaHCO₃ and extracted with CH₂ Cl₂. The organicextracts were combined, dried with Na₂ SO₄, filtered and concentrated invacuo. The product was isolated and purified by preparative TLC (3:1,hexane/acetone) to afford 120 mg. of the title compound as a dark oil.

EXAMPLE 7117-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-hydroxyethoxyethylindol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-t-butyldimethylsilyloxyethoxy-ethylindol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (120 mg) in CH₂ Cl₂ (3 mL.) at rt wasadded a solution of p-toluene sulfonic acid (20 mg.) in CH₃ OH (3 mL.).The reaction mixture was stirred for 3 hr., quenched with saturatedNaHCO₃, then extracted with CH₂ Cl₂. The extracts were combined, driedover Na₂ SO₄, filtered and concentrated in vacuo. The product waspurified by preparative TLC on silica gel (2:1, hexane/acetone) to give51 mg of the title compound. Partial ¹ H NMR (CDCl₃, 200 MHz) δ:7.19 (d,J=9 Hz, 1H); 7.17 (d, J=2 Hz, 1H); 7.08 (d, J=3.5 Hz, 1H); 6.89 (dd, J=2and J=9 Hz, 1H); 6.34 (d, J=3.5 Hz, 1H); 4.22 (t, J=5 Hz, 2H); 3.73 (t,J=5 Hz, 2H); 3.57 (t, J=5 Hz, 2H); 3.39 (t, J=5 Hz, 2H)

EXAMPLE 7217-Ethyl-1,14-dihydroxy-12-[2'-(3"-methoxy-4"-(1'"-(1""-oxoprop-3""-yl)indol-5'"-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a solution of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(3""-hydroxypropyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (700 mg., 0.726 mmol.) in CH₂ Cl₂ (25mL) was added DMSO (2 mL.) and diisopropylethylamine (3.7 mL.) followedby pyridine sulfur trioxide (650 mg., 4.1 mmol.). The mixture wasstirred for 20 min. then poured into saturated aqueous NaHCO₃. Theproduct was extracted into CH₂ Cl₂ which was then dried with Na₂ SO₄,filtered, and concentrated in vacuo. The product was purified by columnchromatography (silica gel, 4:1 hexane/acetone) to give 457 mg. of thetitle compound. Partial ¹ H NMR (CDCl₃, 200 MHz) δ:9.77 (s, 1H); 7.19(d, J=2 Hz, 1H); 7.15 (d, J= 9 Hz, 1H); 7.04 (d, J=3.5 Hz, 1H); 6.89(dd, J=2 and J=9 Hz, 1H); 6.33 (d, J=3.5 Hz, 1H); 4.39 (t, J=5 Hz, 2H);2.94 (t, J=5 Hz, 2H).

EXAMPLE 7317-Ethyl-1,14-dihydroxy-12-[2'-(3"-methoxy-4"-(1'"-(1""-carboxyeth-2""-yl)indol-5'"-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of17-Ethyl-1,14-dihydroxy-12-[2'-(3"-methoxy-4"-(1'"-(1""-oxoprop-3""-yl)indol-5'"-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (100 mg.), 5-bromoindole (300 mg.)and 2-methyl-2-butene (0.80 mL.) in t-butanol (4 mL.) was added asolution of sodium chlorite (15 mg.) and sodium dihydrogen phosphate (15mg.) in water (0.15 mL.). The reaction mixture was stirred for 0.5 hr.then concentrated in vacuo. The residue was partioned between 10 ml.water containing 2 drops of 2N HCl and diethyl ether. The organicextract was dried with Na₂ SO₄, filtered, and concentrated in vacuo. Theproduct was purified by preparative TLC 2× first with 2:1 hexane/acetonethen 7% CH₃ OH in CH₂ Cl₂ and finally flash column chromatography on C₁₈column packing with 60% CH₃ CN in water to give 11 mg. of the titlecompound. Mass (FAB) 1001 (M+Na).

Utilizing the general procedures described in Examples 1 to 73, thefollowing compounds of Formula I (wherein R⁴ is hydrogen, R⁵ is methyl,ethyl, propyl or allyl; R¹⁰ is hydrogen and n is 2) are prepared fromthe appropriately substituted starting materials and reagents.

    ______________________________________                                        EX-                                                                           AM-                                                                           PLE                                                                           NO.   R.sup.1             R.sup.2                                                                              R.sup.3                                                                            R.sup.5                                 ______________________________________                                        74                                                                                   ##STR18##          H      OH   CH.sub.3 CH.sub.2                       75                                                                                   ##STR19##          CH.sub.3                                                                             OH   CH.sub.3 CH.sub.2                       76                                                                                   ##STR20##          CH.sub.3                                                                             OH   CH.sub.3 CH.sub.2                       77                                                                                   ##STR21##          CH.sub.3                                                                             OH   CH.sub.3 CH.sub.2                       78                                                                                   ##STR22##          CH.sub.3                                                                             OH   CH.sub.3 CH.sub.2                       79                                                                                   ##STR23##          CH.sub.3                                                                             OH   CH.sub.3 CH.sub.2                       80                                                                                   ##STR24##          CH.sub.3                                                                             OH   CH.sub.3 CH.sub.2                       81                                                                                   ##STR25##          CH.sub.3                                                                             OH   CH.sub.3 CH.sub.2                       82                                                                                   ##STR26##          CH.sub.3                                                                             OH   CH.sub.3 CH.sub.2                       ______________________________________                                    

EXAMPLE 83 T-Cell Proliferation Assay

1. Sample Preparation

The compounds to be assayed were dissolved in absolute ethanol at 1mg/ml.

2. Assay

Spleens from C57B1/6 mice were taken under sterile conditions and gentlydissociated in ice-cold RPMI 1640 culture medium (GIBC), Grand Island,N.Y.) supplemented with 10% heat-inactivated fetal calf serum (GIBO)).Cells were pelleted by centrifugation at 1500 rpm for 8 minutes.Contaminating red cells were removed by treating the pellet withammonium chloride lysing buffer (GIBO)) for 2 minutes at 4° C. Coldmedium was added and cells were again centrifuged at 1500 rpm for 8minutes. T lymphocytes were then isolated by separation of the cellsuspension on nylon wool columns as follows: Nylon wool columns wereprepared by packing approximately 4 grams of washed and dried nylon woolinto 20 ml plastic syringes. The columns were sterilized by autoclavingat 25° F. for 30 minutes. Nylon wool columns were wetted with warm (37°C.) culture medium and rinsed with the same medium. Washed spleen cellsresuspended in warm medium were slowly applied to the nylon wool. Thecolumns were then incubated in an upright position at 37° C. for 1 hour.Non-adherent T lymphocytes were eluted from the columns with warmculture medium and the cell suspensions were spun as above.

Purified T lymphocytes were resuspended at 2.5×10⁵ cells/ml in completeculture medium composed of RPMI 1640 medium with 10% heat-inactivatedfetal calf serum, 100 mM glutamine, 1 mM sodium pyruvate, 2×10⁻⁵ M2-mercaptoethanol and 50 μg/ml gentamycin. Ionomycin was added at 250ng/ml and PMA at 10 ng/ml. The cell suspension was immediatelydistributed into 96 well flat-bottom microculture plates (Costar) at 200μl/well. The various dilutions of the compound to be tested were thenadded in triplicate wells at 20 μl/well. The compound17-allyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone was used as a standard. The cultureplates were then incubated at 37° C. in a humidified atmosphere of 5%CO₂ -95% air for 44 hours. The proliferation of T lymphocytes wasassessed by measurement of tritiated thymidine incorporation. After 44hours of culturing, the cells were pulse-labelled with 2 μCi/well oftritiated thymidine (NEN, Cambridge, Mass.). After another 4 hours ofincubation, cultures were harvested on glass fiber filters using amultiple sample harvester. Radioactivity of filter discs correspondingto individual wells was measured by standard liquid scintillationcounting methods (Betacounter). Mean counts per minute of replicatewells were calculated and the results expressed as concentration ofcompound required to inhibit tritiated thymidine uptake of T-cells by50%.

A selection of compounds were tested according to the previousprocedure. The title compounds of the following Examples had activity ininhibiting the proliferation of T-cells in the aforementioned assay: 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,23, 26, 28, 31, 32, 33, 34, 35, 37, 39, 42, 44, 46, 47, 48, 49, 50, 51,52, 53, 54, 57, 58, 60, 61, 62, 63, 64, 65, 66, 69, 71, 72 and 73.

The results of this assay are representative of the intrinsicimmunosuppressive activity of the compounds of the present invention.

For determining antagonist activity, the foregoing procedure is modifiedin that dilutions of compounds are cultured with17-ally-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone (as a standard) at a concentration of1.2 nM, a concentration which inhibits T cell proliferation by 100%, theconcentration of compound required to reverse the inhibition obtained bythe standard alone by 50% is measured, and the ED₅₀ value is determined.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe casual variations, adaptations, modifications, deletions, oradditions of procedures and protocols described herein, as come withinthe scope of the following claims and its equivalents.

What is claimed is:
 1. A compound of Formula I: ##STR27## or apharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom:(1) heteroaryl, wherein heteroaryl is selected from the groupconsisting of: ##STR28## wherein Q is --N(X)--, --O--, or --S--; (2)substituted heteroaryl, wherein heteroaryl is as defined above, and inwhich the substituents are X, Y and Z; (3) heteroaryl-C₁₋₁₀ alkyl,wherein heteoaryl is as defined above; (4) substituted heteroaryl-C₁₋₁₀alkyl, wherein heteroaryl is as defined above and in which theheteroaryl group is substituted by X, Y and Z and the alkyl portion maybe substituted with one or more of the substituent(s) selected from:(a)hydroxy, (b) oxo, (c) C₁₋₆ -alkoxy, (d) aryl-C₁₋₃ alkoxy, wherein arylis selected from the group consisting of phenyl and naphthyl, (e)substituted aryl-C₁₋₃ alkoxy, wherein aryl is as defined above and inwhich the substituents on aryl are X, Y and Z, (f) unsubstituted orsubstituted aryloxy, in which the substituents on aryl are X, Y and Z,(g) --OCO--C₁₋₆ alkyl, (h) --NR⁶ R⁷, wherein R⁶ and R⁷ are independentlyselected from(i) hydrogen, (ii) C₁₋₁₀ alkyl unsubstituted or substitutedwith one or more of the substituent(s) selected from:(a') aryl, whereinaryl is as defined above and which is unsubstituted or substituted withX, Y and Z, (b') heteroaryl, wherein heteroaryl is as defined above andwhich is unsubstituted or substituted with X, Y and Z, (c') --OH, (d')C₁₋₆ alkoxy, (e') --CO₂ H, (f') --CO₂ --C₁₋₆ alkyl, (g') --C₃₋₇cycloalkyl, and (h') --OR¹¹, (iii) C₃₋₁₀ alkenyl unsubstituted orsubstituted with one or more of the substituent(s) selected from:(a')aryl, wherein aryl is as defined above and which is unsubstituted orsubstituted with X, Y and Z, (b') heteroaryl, wherein heteroaryl is asdefined above and which is unsubstituted or substituted with X, Y and Z,(c') --OH, (d') C₁₋₆ alkoxy, (e') --CO₂ H, (f') --CO₂ --C₁₋₆ alkyl, (g')--C₃₋₇ cycloalkyl, and (h') --OR¹¹, (iv) or where R⁶ and R⁷ and the N towhich they are attached may form a heterocyclic ring selected from thegroup consisting of: morpholine, thiomorpholine, piperidine, andpiperazine, (i) --NR⁶ CO--C₁₋₆ alkyl-R⁷, wherein R⁶ and R⁷ are asdefined above, (j) --NR⁶ CO₂ --C₁₋₆ alkyl-R⁷, (k) --NR⁶ CONR⁶ R⁷, (l)--OCONR⁶ R⁷, (m) --COOR⁶, (n) --CHO, (o) aryl, wherein aryl is asdefined above, (p) substituted aryl wherein aryl is as defined above andin which the substituents are X, Y and Z, (q) --OR¹¹, and (r) --S(O)_(p)--C₁₋₆ alkyl; (5) heteroaryl-C₁₋₁₀ alkyl wherein heteroaryl is asdefined above and one or more of the alkyl carbons is replaced by agroup selected from: --NR⁶ --, --O--, --S(O)_(p) --, --CO₂ --, --O₂ C--,--CONR⁶ --, --NR⁶ CO--, --NR⁶ CONR⁷ --; (6) substituted heteroaryl-C₁₋₁₀alkyl wherein heteroaryl is as defined above and one or more of thealkyl carbons is replaced by a group selected from: --NR⁶ --, --O--,--S(O)_(p) --, --CO₂ --, --O₂ C--, --CONR⁶ --, --NR⁶ CO--, and --NR⁶CONR⁷ --, the heteroaryl group is substituted with X, Y, and Z, and thealkyl group may be substituted with one or more of the substituent(s)selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) aryl-C₁₋₃alkoxy, wherein aryl is as defined above, (e) substituted aryl-C₁₋₃alkoxy, wherein aryl is as defined above and in which the substituentson aryl are X, Y and Z, (f) unsubstituted or substituted aryloxy,wherein aryl is as defined above and in which the substituents on arylare X, Y and Z, (g) --OCO--C₁₋₆ alkyl, (h) --NR⁶ R⁷, wherein R⁶ and R⁷are as defined above, (i) --NR⁶ CO--C₁₋₆ alkyl-R⁷, (j) --NR⁶ CO₂ --C₁₋₆alkyl-R⁷, (k) --NR⁶ CONR⁶ R⁷, (l) --OCONR⁶ R⁷, (m) --COOR⁶, (n) --CHO,(o) aryl, wherein aryl is as defined above, (p) substituted aryl whereinaryl is as defined above in which the substituents are X, Y and Z, (q)--OR¹¹, and (r) --S(O)_(p) --C₁₋₆ alkyl; (7) heteroaryl-C₃₋₁₀ alkenylwherein heteroaryl is as defined above and alkenyl contains one to fourdouble bonds; (8) heteroaryl-C₃₋₁₀ alkenyl wherein heteroaryl is asdefined above and alkenyl contains one to four double bonds and whereinone or more of the alkyl carbons is replaced by a group selected from:--NR⁶ --, --O--, --S(O)_(p) --, --CO₂ --, --O₂ C--, --CONR⁶ --, --NR⁶CO--, and --NR⁶ CONR⁷ --; (9) substituted heteroaryl-C₃₋₁₀ alkenylwherein heteroaryl is as defined above and alkenyl contains one to fourdouble bonds and wherein one or more of the alkyl carbons may bereplaced by a group selected from: --NR⁶ --, --O--, --S(O)_(p) --, --CO₂--, --O₂ C--, --CONR⁶ --, --NR⁶ CO--, and --NR⁶ CONR⁷, the heteroarylgroup is substituted with X, Y, and Z, and the alkyl group may besubstituted with one or more of the substitutent(s) selected from:(a)hydroxy, (b) oxo, (c) C₁₋₆ alkoxy, (d) aryl-C₁₋₃ alkoxy, wherein aryl isas defined above, (e) substituted aryl-C₁₋₃ alkoxy, wherein aryl is asdefined above and in which the substituents on aryl are X, Y and Z, (f)unsubstituted or substituted aryloxy, wherein aryl is defined above andin which the substituents on aryl are X, Y and Z, (g) --OCO--C₁₋₆ alkyl,(h) --NR⁶ R⁷, wherein R⁶ and R⁷ as defined above, (i) --NR⁶ CO--C₁₋₆alkyl, wherein R⁶ is as defined above, (j) --NR⁶ CO₂ --C₁₋₆ alkyl, (k)--NR⁶ CONR⁶ R⁷, (l) --OCONR⁶ R⁷, (m) --COOR⁶, (n) --CHO, (o) aryl,wherein aryl is as defined above, (p) substituted aryl wherein aryl isas defined above and in which the substituents are X, Y and Z, and (q)--OR¹¹, and (r) --S(O)_(p) --C₁₋₆ alkyl; R² is selected from:(1) thedefinitions of R¹ ; (2) hydrogen; (3) phenyl; (4) substituted phenyl inwhich the substituents are X, Y and Z; (5) 1- or 2-naphthyl; (6)substituted 1- or 2-naphthyl in which the substituents are X, Y and Z;(7) biphenyl; (8) substituted biphenyl in which the substituents are X,Y and Z; (9) C₁₋₁₀ alkyl; (10) substituted-C₁₋₁₀ alkyl in which one ormore substituent(s) is(are) selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆alkoxy, (d) aryl-C₁₋₃ alkoxy, wherein aryl is as defined above, (e)substituted aryl-C₁₋₃ alkoxy, wherein aryl is as defined above and inwhich the substituents on aryl are X, Y and Z, (f) unsubstituted orsubstituted aryloxy, in which the substituents on aryl are X, Y and Z,(g) --OCO--C₁₋₆ alkyl, (h) --NR⁶ R⁷, wherein R⁶ and R⁷ are as definedabove (i) --NR⁶ CO--C₁₋₆ alkyl-R⁷, wherein R⁶ and R⁷ is as definedabove, (j) --COOR⁶, wherein R⁶ is as defined above, (k) --CHO, (l)phenyl, (m) substituted phenyl in which the substituents are X, Y and Z,(n) 1- or 2-naphthyl, (o) substituted 1- or 2-naphthyl in which thesubstituents are X, Y and Z, (p) biphenyl, (q) substituted biphenyl inwhich the substituents are X, Y and Z, (r) --OR¹¹, and (s) --S(O)_(p)--C₁₋₆ alkyl; (11) C₃₋₁₀ alkenyl; (12) substituted C₃₋₁₀ alkenyl inwhich one or more substituent(s) is(are) selected from:(a) hydroxy, (b)oxo, (c) C₁₋₆ alkoxy, (d) phenyl-C₁₋₃ alkoxy,(e) substituted phenyl-C₁₋₃alkoxy, in which the substituents on phenyl are X, Y and Z, (f)--OCO--C₁₋₆ alkyl, (g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above(h) --NR⁶ CO--C₁₋₆ alkyl, wherein R⁶ is as defined above, (i) --COOR⁶,wherein R⁶ is as defined above, (j) --CHO, (k) phenyl, (l) substitutedphenyl in which the substituents are X, Y and Z, (m) 1- or 2-naphthyl,(n) substituted 1- or 2-naphthyl in which the substituents are X, Y andZ, (o) biphenyl, (p) substituted biphenyl in which the substituents areX, Y and Z, (q) --OR¹¹, and (r) --S(O)_(p) --C₁₋₆ alkyl; (13) C₃₋₁₀alkynyl; (14) substituted C₃₋₁₀ alkynyl in which one or moresubstituent(s) is(are) selected from:(a) hydroxy, (b) oxo, (c) C₁₋₆alkoxy, (d) phenyl-C₁₋₃ alkoxy, (e) substituted phenyl-C₁₋₃ alkoxy, inwhich the substituents on phenyl are X, Y and Z, (f) --OCO--C₁₋₆ alkyl,(g) --NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, (h) --NR⁶ CO--C₁₋₆alkyl, wherein R⁶ is as defined above, (i) --COOR⁶, wherein R⁶ is asdefined above, (j) --CHO, (k) phenyl, (l) substituted phenyl in whichthe substituents are X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted1- or 2-naphthyl in which the substituents are X, Y and Z, (o) biphenyl,(p) substituted biphenyl in which the substituents are X, Y and Z, (q)--OR¹¹ ; and (15) --R¹¹ ; R³ is hydrogen, hydroxy, --OR¹¹, or C₁₋₆alkoxy; R⁴ is hydrogen, or R³ and R⁴ taken together form a double bond;R⁵ is methyl, ethyl, propyl or allyl; R¹⁰ is hydrogen, hydroxy, --OR¹¹or fluoro; R¹¹ is selected from:(a) --PO(OH)O⁻ M⁺, wherein M⁺ is apositively charged inorganic or organic counterion selected from thegroup consisting of: ammonium, sodium, lithium, potassium, calcium,magnesium, dicyclohexylamine, N-methyl-D-glucamine, arginine and lysine,(b) --SO₃ ⁻ M⁺, (c) --CO(CH₂)_(q) CO₂ ⁻ M⁺, wherein q is 1-3, and (d)--CO--C₁₋₆ alkyl-NR⁶ R⁷, wherein R⁶ and R⁷ are as defined above and thealkyl is unsubstituted or substituted with one or more substituentsselected from:(i) hydroxy, (ii) C₁₋₆ alkoxy, (iii) --NR¹⁶ R¹⁷, whereinR¹⁶ and R¹⁷ are independently selected from:(a') hydrogen, and (b') C₁₋₆alkyl, (iv) --COOR⁶, wherein R⁶ is as defined above, (v) phenyl, (iv)substituted phenyl in which the substituents are X, Y and Z, (vii)heteroaryl, wherein heteroaryl is as defined above, (viii) --SH, and(ix) --S--C₁₋₆ alkyl; W is O or (H, OH); X, Y and Z independently areselected from:(a) hydrogen, (b) C₁₋₁₀ alkyl, unsubstituted orsubstituted with one or more substituents selected from:(i) aryl,wherein aryl is as defined above, (ii) substituted aryl wherein aryl isas defined above and in which the substituents are X', Y' and Z', (iii)heteroaryl, wherein heteroaryl is as defined above, (iv) substitutedheteroaryl wherein heteroaryl is as defined above and in which thesubstituents are X', Y', and Z', (v) unsubstituted or substitutedaryloxy, wherein aryl is as defined above and in which the substituentson aryl are X', Y' and Z', (vi) --OR⁶, (vii) --OR¹¹, (viii) --OCOR⁶,(ix) --OCO₂ R⁶, (x) --NR⁶ R⁷, (xi) --CHO, (xii) --NR⁶ COC₁₋₆ alkyl-R⁷,(xiii) --NR⁶ CO₂ C₁₋₆ alkyl-R⁷, (xiv) --NR⁶ CONR⁶ R⁷, (xv) --OCONR⁶ R⁷,(xvi) --CONR⁶ R⁷, (c) C₁₋₁₀ alkyl wherein one or more of the alkylcarbons is replaced by a group selected from --NR⁶ --, --O--, --S(O)_(p)--, --CO₂ --, --O₂ C--, --CONR⁶ --, --NR⁶ CO--, --NR⁶ CONR⁷ --, --CO--,--CH(OH)--, alkenyl or alkynyl and the alkyl may be unsubstituted orsubstituted with one or more substituents selected from:(i) aryl,wherein aryl is as defined above, (ii) substituted aryl wherein aryl isas defined above and in which the substituents are X', Y' and Z', (iii)heteroaryl, wherein heteroaryl is as defined above, (iv) substitutedheteroaryl wherein heteroaryl is as defined above and in which thesubstituents are X', Y', and Z', (v) unsubstituted or substitutedaryloxy, wherein aryl is as defined above and in which the substituentson aryl are X', Y', and Z', (vi) --OR⁶, (vii) --OR¹¹, (viii) --OCOR⁶,(ix) --OCO₂ R⁶, (x) --NR⁶ R⁷, (xi) --CHO (xii) --NR⁶ COC₁₋₆ alkyl-R⁷,(xiii) --NR⁶ CO₂ C₁₋₆ alkyl-R⁷, (xiv) --NR⁶ CONR⁶ R⁷, (xv) --OCONR⁶ R⁷,(xvi) --CONR⁶ R⁷, (d) halogen, (e) --NR⁶ R⁷, (f) --CN, (g) --CHO, (h)--CF₃, (i) --SR⁸, wherein R⁸ is hydrogen, C₁₋₆ alkyl, trifluoromethyl,or phenyl, (j) --SOR⁸, (k) --SO₂ R⁸, (l) --CONR⁶ R⁷, (m) R⁹ O(CH₂)_(m)--wherein R⁹ is hydrogen, C₁₋₆ alkyl, hydroxy-C₂₋₃ alkyl, --CF₃, phenyl,R¹¹ or naphthyl and m is 0, 1, 2, or 3, (n) --CH(OR¹²)(OR¹³), whereinR¹² and R¹³ are C₁₋₃ alkyl or taken together form an ethyl or propylbridge, (o) ##STR29## wherein R⁹ and m are as defined above, (p)##STR30## wherein R⁹ and m are as defined above, and (q) --R¹¹ ; or anytwo of X, Y and Z may be joined to form a saturated ring having 5, 6 or7 ring atoms, said ring atoms comprising 1 or 2 oxygen atoms, theremaining ring atoms being carbon, X', Y' and Z' independently areselected from:(a) hydrogen, (b) C₁₋₇ alkyl, (c) C₂₋₆ alkenyl, (d)halogen, (e) --(CH₂)_(m) --NR⁶ R⁷, wherein R⁶, R⁷ and m are as definedabove, (f) --CN, (g) --CHO, (h) --CF₃, (i) --SR⁸, wherein R⁸ ishydrogen, C₁₋₆ alkyl, trifluoromethyl, or phenyl, (j) --SOR⁸, wherein R⁸is as defined above, (k) --SO₂ R⁸, wherein R⁸ is as defined above, (l)--CONR⁶ R⁷, wherein R⁶ and R⁷ are as defined above, (m) R⁹ O(CH₂)_(m)--wherein R⁹ and m are as defined above, (n) --CH(OR¹²)(OR¹³), whereinR¹² and R¹³ are as defined above, (o) ##STR31## wherein R⁹ and m are asdefined above, (p) ##STR32## wherein R⁹ and m are as defined above, and(q) --R¹¹ ; n is 1 or
 2. 2. The compound according to claim 1 whereinthe absolute configuration of Formula I is as defined in Formula III:##STR33##
 3. The compound of claim 1, wherein the heteroaryl is selectedfrom the group consisting of: ##STR34## wherein X is defined in claim 1.4. The compound of claim 1, wherein heteroaryl is: ##STR35## R² isselected from: (1) hydrogen,(2) methyl, (3) ethyl, (4) propyl, (5)allyl, (6) R¹¹, (7) --C₂₋₃ alkyl-OH; and (8) --C₂₋₃ alkyl-OR¹¹ ; R³ isselected from:(1) hydrogen, (2) hydroxy, (3) --OR¹¹, or R³ and R⁴ takentogether form a double bond; R¹⁰ is hydrogen, hydroxy, fluoro, or --OR¹¹; W is 0; and n is
 2. 5. A compound which is selected from the groupconsisting of: ##STR36## or a pharmaceutically acceptable salt thereof,wherein R^(6a) is H or CH₃ and the definitions of R², R³, R⁵, R⁶ and R⁷are selected from the following groups of substituents:

    ______________________________________                                        R.sup.6     R.sup.7       R.sup.2                                                                              R.sup.3                                                                             R.sup.5                                ______________________________________                                        phenyl      phenyl        CH.sub.3                                                                             OH    ethyl                                  phenyl      H             CH.sub.3                                                                             OH    ethyl                                  benzyl      H             CH.sub.3                                                                             OH    ethyl                                  4-HO.sub.2 C-benzyl                                                                       H             CH.sub.3                                                                             OH    ethyl                                  4-H.sub.2 NCO-benzyl                                                                      H             CH.sub.3                                                                             OH    ethyl                                  4-(CH.sub.3)O-benzyl                                                                      H             CH.sub.3                                                                             OH    ethyl                                  4-HO-benzyl H             CH.sub.3                                                                             OH    ethyl                                  4-Cl-benzyl H             CH.sub.3                                                                             OH    ethyl                                  4-(CH.sub.3).sub.2 N-benzyl                                                               H             CH.sub.3                                                                             OH    ethyl                                  3-HO.sub.2 C-benzyl                                                                       H             CH.sub.3                                                                             OH    ethyl                                  3-H.sub.2 NCO-benzyl                                                                      H             CH.sub.3                                                                             OH    ethyl                                  3-CH.sub.3 O-benzyl                                                                       H             CH.sub.3                                                                             OH    ethyl                                  3-HO-benzyl H             CH.sub.3                                                                             OH    ethyl                                  3-Cl-benzyl H             CH.sub.3                                                                             OH    ethyl                                  3-(CH.sub.3).sub.2 N-benzyl                                                               H             CH.sub.3                                                                             OH    ethyl                                  4-pyridyl   H             CH.sub.3                                                                             OH    ethyl                                  3-pyridyl   H             CH.sub.3                                                                             OH    ethyl                                  2-pyridyl   H             CH.sub.3                                                                             OH    ethyl                                  4-pyridylmethyl                                                                           H             CH.sub.3                                                                             OH    ethyl                                  3-pyridylmethyl                                                                           H             CH.sub.3                                                                             OH    ethyl                                  2-pyridylmethyl                                                                           H             CH.sub.3                                                                             OH    ethyl                                  phenyl      phenyl        CH.sub.3                                                                             H     ethyl                                  phenyl      H             CH.sub.3                                                                             H     ethyl                                  benzyl      H             CH.sub.3                                                                             H     ethyl                                  4-HO.sub.2 C-benzyl                                                                       H             CH.sub.3                                                                             H     ethyl                                  4-H.sub.2 NCO-benzyl                                                                      H             CH.sub. 3                                                                            H     ethyl                                  4-CH.sub.3 O-benzyl                                                                       H             CH.sub.3                                                                             H     ethyl                                  4-HO-benzyl H             CH.sub.3                                                                             H     ethyl                                  4-Cl-benzyl H             CH.sub.3                                                                             H     ethyl                                  4-(CH.sub.3).sub.2 N-benzyl                                                               H             CH.sub.3                                                                             H     ethyl                                  3-HO.sub.2 C-benzyl                                                                       H             CH.sub.3                                                                             H     ethyl                                  3-H.sub.2 NCO-benzyl                                                                      H             CH.sub.3                                                                             H     ethyl                                  3-CH.sub.3 O-benzyl                                                                       H             CH.sub.3                                                                             H     ethyl                                  3-HO-benzyl H             CH.sub.3                                                                             H     ethyl                                  3-Cl-benzyl H             CH.sub.3                                                                             H     ethyl                                  3-(CH.sub.3).sub.2 N-benzyl                                                               H             CH.sub.3                                                                             H     ethyl                                  4-pyridyl   H             CH.sub.3                                                                             H     ethyl                                  3-pyridyl   H             CH.sub.3                                                                             H     ethyl                                  2-pyridyl   H             CH.sub.3                                                                             H     ethyl                                  4-pyridylmethyl                                                                           H             CH.sub.3                                                                             H     ethyl                                  3-pyridylmethyl                                                                           H             CH.sub.3                                                                             H     ethyl                                  2-pyridylmethyl                                                                           H             CH.sub.3                                                                             H     ethyl                                  phenyl      phenyl        CH.sub.3                                                                             OH    allyl                                  phenyl      H             CH.sub.3                                                                             OH    allyl                                  benzyl      H             CH.sub.3                                                                             OH    allyl                                  4-HO.sub.2 C-benzyl                                                                       H             CH.sub.3                                                                             OH    allyl                                  4-H.sub.2 NCO-benzyl                                                                      H             CH.sub.3                                                                             OH    allyl                                  4-CH.sub.3 O-benzyl                                                                       H             CH.sub.3                                                                             OH    allyl                                  4-HO-benzyl H             CH.sub.3                                                                             OH    allyl                                  4-Cl-benzyl H             CH.sub.3                                                                             OH    allyl                                  4-(CH.sub.3).sub.2 N-benzyl                                                               H             CH.sub.3                                                                             OH    allyl                                  3-HO.sub.2 C-benzyl                                                                       H             CH.sub.3                                                                             OH    allyl                                  3-H.sub.2 NCO-benzyl                                                                      H             CH.sub.3                                                                             OH    allyl                                  3-CH.sub.3 O-benzyl                                                                       H             CH.sub. 3                                                                            OH    allyl                                  3-HO-benzyl H             CH.sub.3                                                                             OH    allyl                                  3-Cl-benzyl H             CH.sub.3                                                                             OH    allyl                                  3-(CH.sub.3).sub.2 N-benzyl                                                               H             CH.sub.3                                                                             OH    allyl                                  4-pyridyl   H             CH.sub.3                                                                             OH    allyl                                  3-pyridyl   H             CH.sub.3                                                                             OH    allyl                                  2-pyridyl   H             CH.sub.3                                                                             OH    allyl                                  4-pyridylmethyl                                                                           H             CH.sub.3                                                                             OH    allyl                                  3-pyridylmethyl                                                                           H             CH.sub.3                                                                             OH    allyl                                  2-pyridylmethyl                                                                           H             CH.sub.3                                                                             OH    allyl                                  CH.sub.3    H             CH.sub.3                                                                             OH    allyl                                  CH.sub.3 CH.sub.2                                                                         H             CH.sub.3                                                                             OH    allyl                                  CH.sub.3 CH.sub.2 CH.sub.2                                                                H             CH.sub.3                                                                             OH    allyl                                  (CH.sub.3).sub.2 CH                                                                       H             CH.sub.3                                                                             OH    allyl                                  HO.sub.2 CCH.sub.2 CH.sub.2                                                               H             CH.sub.3                                                                             OH    allyl                                  H.sub.2 NCOCH.sub.2 CH.sub.2                                                              H             CH.sub.3                                                                             OH    allyl                                  HOCH.sub.2 CH.sub.2                                                                       H             CH.sub.3                                                                             OH    allyl                                  HOCH.sub.2 CH.sub.2 CH.sub.2                                                              H             CH.sub.3                                                                             OH    allyl                                  CH.sub.3    CH.sub.3      CH.sub.3                                                                             OH    ethyl                                  CH.sub.3 CH.sub.2                                                                         CH.sub.3 CH.sub.2                                                                           CH.sub.3                                                                             OH    ethyl                                  CH.sub.3 CH.sub.2 CH.sub.2                                                                CH.sub.3 CH.sub.2 CH.sub.2                                                                  CH.sub.3                                                                             OH    ethyl                                  HOCH.sub.2 CH.sub.2                                                                       HOCH.sub.2 CH.sub.2                                                                         CH.sub.3                                                                             OH    ethyl                                  HOCH.sub.2 CH.sub.2 CH.sub.2                                                              HOCH.sub.2 CH.sub.2 CH.sub.2                                                                CH.sub.3                                                                             OH    ethyl                                  CH.sub.3    H             CH.sub.3                                                                             H     ethyl                                  CH.sub.3 CH.sub.2                                                                         H             CH.sub.3                                                                             H     ethyl                                  CH.sub.3 CH.sub.2 CH.sub.2                                                                H             CH.sub.3                                                                             H     ethyl                                  (CH.sub.3).sub.2 CH                                                                       H             CH.sub.3                                                                             H     ethyl                                  HO.sub.2 CCH.sub.2 CH.sub.2                                                               H             CH.sub.3                                                                             H     ethyl                                  H.sub.2 NCOCH.sub.2 CH.sub.2                                                              H             CH.sub.3                                                                             H     ethyl                                  HOCH.sub.2 CH.sub.2                                                                       H             CH.sub.3                                                                             H     ethyl                                  HOCH.sub.2 CH.sub.2 CH.sub.2                                                              H             CH.sub.3                                                                             H     ethyl                                  CH.sub.3    CH.sub.3      CH.sub.3                                                                             H     ethyl                                  CH.sub.3 CH.sub.2                                                                         CH.sub.3 CH.sub.2                                                                           CH.sub.3                                                                             H     ethyl                                  CH.sub.3 CH.sub.2 CH.sub.2                                                                CH.sub.3 CH.sub.2 CH.sub.2                                                                  CH.sub.3                                                                             H     ethyl                                  HOCH.sub.2 CH.sub.2                                                                       HOCH.sub.2 CH.sub.2                                                                         CH.sub.3                                                                             H     ethyl                                  HOCH.sub.2 CH.sub.2 CH.sub.2                                                              HOCH.sub.2 CH.sub.2 CH.sub.2                                                                CH.sub.3                                                                             H     ethyl                                  CH.sub.3    H             H      OH    ethyl                                  CH.sub.3 CH.sub.2                                                                         H             H      OH    ethyl                                  CH.sub.3 CH.sub.2 CH.sub.2                                                                H             H      OH    ethyl                                  (CH.sub.3).sub.2 CH                                                                       H             H      OH    ethyl                                  HO.sub.2 CCH.sub.2 CH.sub.2                                                               H             H      OH    ethyl                                  H.sub.2 NCOCH.sub.2 CH.sub.2                                                              H             H      OH    ethyl                                  HOCH.sub.2 CH.sub.2                                                                       H             H      OH    ethyl                                  HOCH.sub.2 CH.sub.2 CH.sub.2                                                              H             H      OH    ethyl                                  CH.sub.3    CH.sub.3      H      OH    ethyl                                  CH.sub.3 CH.sub.2                                                                         CH.sub.3 CH.sub.2                                                                           H      OH    ethyl                                  CH.sub.3 CH.sub.2 CH.sub.2                                                                CH.sub.3 CH.sub.2 CH.sub.2                                                                  H      OH    ethyl                                  HOCH.sub.2 CH.sub.2                                                                       HOCH.sub.2 CH.sub.2                                                                         H      OH    ethyl                                  HOCH.sub.2 CH.sub.2 CH.sub.2                                                              HOCH.sub.2 CH.sub.2 CH.sub.2                                                                H      OH    ethyl                                  --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --                                                           CH.sub.3                                                                             H       ethyl                                    --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                   CH.sub.3                                                                             H       ethyl                                    --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --                                                           CH.sub.3                                                                             OH      ethyl                                    --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                   H      OH      ethyl                                    --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --                                                           H      OH      ethyl                                    --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                   H      OH      ethyl                                    --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --                                                           CH.sub.3                                                                             H       allyl                                    --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                   CH.sub.3                                                                             H       allyl                                    --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --                                                           CH.sub.3                                                                             OH      allyl                                    --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                   H      OH      allyl                                    --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --                                                           H      OH      allyl                                    --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                   H      OH      allyl.                                   ______________________________________                                    


6. A compound which is selected from the group consisting of: ##STR37##or a pharmaceutically acceptable salt thereof, wherein R^(6a) is H orCH₃ and R², R³, R⁵ and R⁶ are selected from the following groups ofsubstituents:

    ______________________________________                                        R.sup.6         R.sup.2   R.sup.3  R.sup.5                                    ______________________________________                                        H               CH.sub.3  OH       ethyl                                      CH.sub.3        CH.sub.3  OH       ethyl                                      CH.sub.3 CH.sub.2                                                                             CH.sub.3  OH       ethyl                                      CH.sub.2 ═CHCH.sub.2                                                                      CH.sub.3  OH       ethyl                                      CH.sub.3 CH.sub.2 CH.sub.2                                                                    CH.sub.3  OH       ethyl                                      (CH.sub.3).sub.2 CH                                                                           CH.sub.3  OH       ethyl                                      HO.sub.2 CCH.sub.2 CH.sub.2                                                                   CH.sub.3  OH       ethyl                                      H.sub.2 NCOCH.sub.2 CH.sub.2                                                                  CH.sub.3  OH       ethyl                                      HOCH.sub.2 CH.sub.2                                                                           CH.sub.3  OH       ethyl                                      HOCH.sub.2 CH.sub.2 CH.sub.2                                                                  CH.sub.3  OH       ethyl                                      (CH.sub.3).sub.2 CH.sub.2                                                                     CH.sub.3  OH       ethyl                                      phenyl          CH.sub.3  OH       ethyl                                      4-pyridyl       CH.sub.3  OH       ethyl                                      3-pyridyl       CH.sub.3  OH       ethyl                                      2-pyridyl       CH.sub.3  OH       ethyl                                      4-pyridylmethyl CH.sub.3  OH       ethyl                                      3-pyridylmethyl CH.sub.3  OH       ethyl                                      2-pyridylmethyl CH.sub.3  OH       ethyl                                      benzyl          CH.sub.3  OH       ethyl                                      4-HO.sub.2 C-benzyl                                                                           CH.sub.3  OH       ethyl                                      4-H.sub.2 NCO-benzyl                                                                          CH.sub.3  OH       ethyl                                      4-CH.sub.3 O-benzyl                                                                           CH.sub.3  OH       ethyl                                      4-HO-benzyl     CH.sub.3  OH       ethyl                                      4-Cl-benzyl     CH.sub.3  OH       ethyl                                      4-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  OH       ethyl                                      3-HO.sub.2 C-benzyl                                                                           CH.sub.3  OH       ethyl                                      3-H.sub.2 NCO-benzyl                                                                          CH.sub.3  OH       ethyl                                      3-CH.sub.3 -benzyl                                                                            CH.sub.3  OH       ethyl                                      3-HO-benzyl     CH.sub.3  OH       ethyl                                      3-Cl-benzyl     CH.sub.3  OH       ethyl                                      3-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  OH       ethyl                                      2-HO-benzyl     CH.sub.3  OH       ethyl                                      2-Cl-benzyl     CH.sub.3  OH       ethyl                                      2-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  OH       ethyl                                      CH.sub.3        CH.sub.3  H        ethyl                                      CH.sub.3 CH.sub.2                                                                             CH.sub.3  H        ethyl                                      CH.sub.2 ═CHCH.sub.2                                                                      CH.sub.3  H        ethyl                                      CH.sub.3 CH.sub.2 CH.sub.2                                                                    CH.sub.3  H        ethyl                                      (CH.sub.3).sub.2 CH                                                                           CH.sub.3  H        ethyl                                      HO.sub.2 CCH.sub.2 CH.sub.2                                                                   CH.sub.3  H        ethyl                                      H.sub.2 NCOCH.sub.2 CH.sub.2                                                                  CH.sub.3  H        ethyl                                      HOCH.sub.2 CH.sub.2                                                                           CH.sub.3  H        ethyl                                      HOCH.sub.2 CH.sub.2 CH.sub.2                                                                  CH.sub.3  H        ethyl                                      (CH.sub.3).sub.2 CH.sub.2                                                                     CH.sub.3  H        ethyl                                      phenyl          CH.sub.3  H        ethyl                                      4-pyridyl       CH.sub.3  H        ethyl                                      3-pyridyl       CH.sub.3  H        ethyl                                      2-pyridyl       CH.sub.3  H        ethyl                                      4-pyridylmethyl CH.sub.3  H        ethyl                                      3-pyridylmethyl CH.sub.3  H        ethyl                                      2-pyridylmethyl CH.sub.3  H        ethyl                                      benzyl          CH.sub.3  H        ethyl                                      4-HO.sub.2 C-benzyl                                                                           CH.sub.3  H        ethyl                                      4-H.sub.2 NCO-benzyl                                                                          CH.sub.3  H        ethyl                                      4-CH.sub.3 O-benzyl                                                                           CH.sub.3  H        ethyl                                      4-HO-benzyl     CH.sub.3  H        ethyl                                      4-Cl-benzyl     CH.sub.3  H        ethyl                                      4-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  H        ethyl                                      3-HO.sub.2 C-benzyl                                                                           CH.sub.3  H        ethyl                                      3-H.sub.2 NCO-benzyl                                                                          CH.sub.3  H        ethyl                                      3-CH.sub.3 O-benzyl                                                                           CH.sub.3  H        ethyl                                      3-HO-benzyl     CH.sub.3  H        ethyl                                      3-Cl-benzyl     CH.sub.3  H        ethyl                                      3-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  H        ethyl                                      2-HO.sub.2 C-benzyl                                                                           CH.sub.3  H        ethyl                                      2-H.sub.2 NCO-benzyl                                                                          CH.sub.3  H        ethyl                                      2-CH.sub.3 O-benzyl                                                                           CH.sub.3  H        ethyl                                      2-HO-benzyl     CH.sub.3  H        ethyl                                      2-Cl-benzyl     CH.sub.3  H        ethyl                                      2-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  H        ethyl                                      CH.sub.3        CH.sub.3  OH       allyl                                      CH.sub.3 CH.sub.2                                                                             CH.sub.3  OH       allyl                                      CH.sub.2 ═CHCH.sub.2                                                                      CH.sub.3  OH       allyl                                      CH.sub.3 CH.sub.2 CH.sub.2                                                                    CH.sub.3  OH       allyl                                      (CH.sub.3).sub.2 CH                                                                           CH.sub.3  OH       allyl                                      HO.sub.2 CCH.sub.2 CH.sub.2                                                                   CH.sub.3  OH       allyl                                      H.sub.2 NCOCH.sub.2 CH.sub.2                                                                  CH.sub.3  OH       allyl                                      HOCH.sub.2 CH.sub.2                                                                           CH.sub.3  OH       allyl                                      HOCH.sub.2 CH.sub.2 CH.sub.2                                                                  CH.sub.3  OH       allyl                                      (CH.sub.3).sub.2 CH.sub.2                                                                     CH.sub.3  OH       allyl                                      phenyl          CH.sub.3  OH       allyl                                      4-pyridyl       CH.sub. 3 OH       allyl                                      3-pyridyl       CH.sub.3  OH       allyl                                      2-pyridyl       CH.sub.3  OH       allyl                                      4-pyridylmethyl CH.sub.3  OH       allyl                                      3-pyridylmethyl CH.sub.3  OH       allyl                                      2-pyridylmethyl CH.sub.3  OH       allyl                                      benzyl          CH.sub.3  OH       allyl                                      4-HO.sub.2 C-benzyl                                                                           CH.sub.3  OH       allyl                                      4-H.sub.2 NCO-benzyl                                                                          CH.sub.3  OH       allyl                                      4-CH.sub.3 O-benzyl                                                                           CH.sub.3  OH       allyl                                      4-HO-benzyl     CH.sub.3  OH       allyl                                      4-Cl-benzyl     CH.sub.3  OH       allyl                                      4-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  OH       allyl                                      3-HO.sub.2 C-benzyl                                                                           CH.sub.3  OH       allyl                                      3-H.sub.2 NCO-benzyl                                                                          CH.sub.3  OH       allyl                                      3-CH.sub.3 O-benzyl                                                                           CH.sub.3  OH       allyl                                      3-HO-benzyl     CH.sub.3  OH       allyl                                      3-Cl-benzyl     CH.sub.3  OH       allyl                                      3-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  OH       allyl                                      2-HO.sub.2 C-benzyl                                                                           CH.sub.3  OH       allyl                                      2-H.sub.2 NCO-benzyl                                                                          CH.sub.3  OH       allyl                                      2-CH.sub.3 O-benzyl                                                                           CH.sub.3  OH       allyl                                      2-HO-benzyl     CH.sub.3  OH       allyl                                      2-Cl-benzyl     CH.sub.3  OH       allyl                                      2-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  OH       allyl.                                     ______________________________________                                    


7. A compound which is selected from the group consisting of: ##STR38##or a pharmaceutically acceptable salt thereof, wherein R^(6a) is H orCH₃ and R^(a), R², R³ and R⁵ are selected from the following groups ofsubstituents:

    ______________________________________                                        R.sup.a         R.sup.2   R.sup.3  R.sup.5                                    ______________________________________                                        CH.sub.3        CH.sub.3  OH       ethyl                                      CH.sub.3 CH.sub.2                                                                             CH.sub.3  OH       ethyl                                      CH.sub.2 ═CHCH.sub.2                                                                      CH.sub.3  OH       ethyl                                      CH.sub.3 CH.sub.2 CH.sub.2                                                                    CH.sub.3  OH       ethyl                                      (CH.sub.3).sub.2 CH                                                                           CH.sub.3  OH       ethyl                                      HO.sub.2 CCH.sub.2 CH.sub.2                                                                   CH.sub.3  OH       ethyl                                      H.sub.2 NCOCH.sub.2 CH.sub.2                                                                  CH.sub.3  OH       ethyl                                      HOCH.sub.2 CH.sub.2                                                                           CH.sub.3  OH       ethyl                                      HOCH.sub.2 CH.sub.2 CH.sub.2                                                                  CH.sub.3  OH       ethyl                                      (CH.sub.3).sub.2 CH.sub.2                                                                     CH.sub.3  OH       ethyl                                      phenyl          CH.sub.3  OH       ethyl                                      4-pyridyl       CH.sub.3  OH       ethyl                                      3-pyridyl       CH.sub.3  OH       ethyl                                      2-pyridyl       CH.sub.3  OH       ethyl                                      4-pyridylmethyl CH.sub.3  OH       ethyl                                      3-pyridylmethyl CH.sub.3  OH       ethyl                                      2-pyridylmethyl CH.sub.3  OH       ethyl                                      benzyl          CH.sub.3  OH       ethyl                                      4-HO.sub.2 C-benzyl                                                                           CH.sub.3  OH       ethyl                                      4-H.sub.2 NCO-benzyl                                                                          CH.sub.3  OH       ethyl                                      3-CH.sub.3 O-benzyl                                                                           CH.sub.3  OH       ethyl                                      4-HO-benzyl     CH.sub.3  OH       ethyl                                      4-Cl-benzyl     CH.sub.3  OH       ethyl                                      4-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  OH       ethyl                                      3-HO.sub.2 C-benzyl                                                                           CH.sub.3  OH       ethyl                                      3-H.sub.2 NCO-benzyl                                                                          CH.sub. 3 OH       ethyl                                      3-CH.sub.3 O-benzyl                                                                           CH.sub.3  OH       ethyl                                      3-HO-benzyl     CH.sub.3  OH       ethyl                                      3-Cl-benzyl     CH.sub.3  OH       ethyl                                      3-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  OH       ethyl                                      2-HO.sub.2 C-benzyl                                                                           CH.sub.3  OH       ethyl                                      2-H.sub.2 NCO-benzyl                                                                          CH.sub.3  OH       ethyl                                      2-CH.sub.3 O-benzyl                                                                           CH.sub.3  OH       ethyl                                      2-HO-benzyl     CH.sub.3  OH       ethyl                                      2-Cl-benzyl     CH.sub.3  OH       ethyl                                      2-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  OH       ethyl                                      CH.sub.3        CH.sub.3  H        ethyl                                      CH.sub.3 CH.sub.2                                                                             CH.sub.3  H        ethyl                                      CH.sub.2 ═CHCH.sub.2                                                                      CH.sub.3  H        ethyl                                      CH.sub.3 CH.sub.2 CH.sub.2                                                                    CH.sub.3  H        ethyl                                      (CH.sub.3).sub.2 CH                                                                           CH.sub.3  H        ethyl                                      HO.sub.2 CCH.sub.2 CH.sub.2                                                                   CH.sub.3  H        ethyl                                      H.sub.2 NCOCH.sub.2 CH.sub.2                                                                  CH.sub.3  H        ethyl                                      HOCH.sub.2 CH.sub.2                                                                           CH.sub.3  H        ethyl                                      HOCH.sub.2 CH.sub.2 CH.sub.2                                                                  CH.sub.3  H        ethyl                                      (CH.sub.3).sub.2 CH.sub.2                                                                     CH.sub.3  H        ethyl                                      phenyl          CH.sub.3  H        ethyl                                      4-pyridyl       CH.sub.3  H        ethyl                                      3-pyridyl       CH.sub.3  H        ethyl                                      2-pyridyl       CH.sub.3  H        ethyl                                      4-pyridylmethyl CH.sub.3  H        ethyl                                      3-pyridylmethyl CH.sub.3  H        ethyl                                      2-pyridylmethyl CH.sub.3  H        ethyl                                      benzyl          CH.sub.3  H        ethyl                                      4-HO.sub. 2 C-benzyl                                                                          CH.sub.3  H        ethyl                                      4-H.sub.2 NCO-benzyl                                                                          CH.sub.3  H        ethyl                                      4-CH.sub.3 O-benzyl                                                                           CH.sub.3  H        ethyl                                      4-HO-benzyl     CH.sub.3  H        ethyl                                      4-Cl-benzyl     CH.sub.3  H        ethyl                                      4-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  H        ethyl                                      3-HO.sub.2 C-benzyl                                                                           CH.sub.3  H        ethyl                                      3-H.sub.2 NCO-benzyl                                                                          CH.sub.3  H        ethyl                                      3-(CH.sub.3 O-benzyl                                                                          CH.sub.3  H        ethyl                                      3-HO-benzyl     CH.sub.3  H        ethyl                                      3-Cl-benzyl     CH.sub.3  H        ethyl                                      3-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  H        ethyl                                      2-HO.sub.2 C-benzyl                                                                           CH.sub.3  H        ethyl                                      2-H.sub.2 NCO-benzyl                                                                          CH.sub.3  H        ethyl                                      2-CH.sub.3 O-benzyl                                                                           CH.sub.3  H        ethyl                                      2-HO-benzyl     CH.sub.3  H        ethyl                                      2-Cl-benzyl     CH.sub.3  H        ethyl                                      2-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  H        ethyl                                      CH.sub.3        CH.sub.3  OH       allyl                                      CH.sub.3 CH.sub.2                                                                             CH.sub.3  OH       allyl                                      CH.sub.2 ═CHCH.sub.2                                                                      CH.sub.3  OH       allyl                                      CH.sub.3 CH.sub.2 CH.sub.2                                                                    CH.sub.3  OH       allyl                                      (CH.sub.3).sub.2 CH                                                                           CH.sub.3  OH       allyl                                      HO.sub.2 CCH.sub.2 CH.sub.2                                                                   CH.sub.3  OH       allyl                                      H.sub.2 NCOCH.sub.2 CH.sub.2                                                                  CH.sub.3  OH       allyl                                      HOCH.sub.2 CH.sub.2                                                                           CH.sub.3  OH       allyl                                      HOCH.sub.2 CH.sub.2 CH.sub.2                                                                  CH.sub.3  OH       allyl                                      (CH.sub. 3).sub.2 CH.sub.2                                                                    CH.sub.3  OH       allyl                                      phenyl          CH.sub.3  OH       allyl                                      4-pyridyl       CH.sub.3  OH       allyl                                      3-pyridyl       CH.sub.3  OH       allyl                                      2-pyridyl       CH.sub.3  OH       allyl                                      4-pyridylmethyl CH.sub.3  OH       allyl                                      3-pyridylmethyl CH.sub.3  OH       allyl                                      2-pyridylmethyl CH.sub.3  OH       allyl                                      benzyl          CH.sub.3  OH       allyl                                      4-HO.sub.2 C-benzyl                                                                           CH.sub.3  OH       allyl                                      4-H.sub.2 NCO-benzyl                                                                          CH.sub.3  OH       allyl                                      4-CH.sub.3 O-benzyl                                                                           CH.sub.3  OH       allyl                                      4-HO-benzyl     CH.sub.3  OH       allyl                                      4-Cl-benzyl     CH.sub.3  OH       allyl                                      4-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  OH       allyl                                      3-HO.sub.2 C-benzyl                                                                           CH.sub.3  OH       allyl                                      3-H.sub.2 NCO-benzyl                                                                          CH.sub.3  OH       allyl                                      3-CH.sub.3 O-benzyl                                                                           CH.sub.3  OH       allyl                                      3-HO-benzyl     CH.sub.3  OH       allyl                                      3-Cl-benzyl     CH.sub.3  OH       allyl                                      3-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  OH       allyl                                      2-HO.sub.2 C-benzyl                                                                           CH.sub.3  OH       allyl                                      2-H.sub.2 NCO-benzyl                                                                          CH.sub.3  OH       allyl                                      2-CH.sub.3 O-benzyl                                                                           CH.sub.3  OH       allyl                                      2-HO-benzyl     CH.sub.3  OH       allyl                                      2-Cl-benzyl     CH.sub.3  OH       allyl                                      2-(CH.sub.3).sub.2 N-benzyl                                                                   CH.sub.3  OH       allyl.                                     ______________________________________                                    


8. A compound which is: ##STR39## or a pharmaceutically acceptable saltthereof, wherein X, R², R³ and R⁵ are selected from the following groupsof substituents:

    ______________________________________                                        X                      R.sup.2                                                                              R.sup.3 R.sup.5                                 ______________________________________                                        1-imidazolylmethyl     CH.sub.3                                                                             OH      ethyl                                   2-imidazolylmethyl     CH.sub.3                                                                             OH      ethyl                                   3-thiazolylmethyl      CH.sub.3                                                                             OH      ethyl                                   2-thiazolylmethyl      CH.sub.3                                                                             OH      ethyl                                   2-oxazolylmethyl       CH.sub.3                                                                             OH      ethyl                                   5-tetrazolymethyl      CH.sub.3                                                                             OH      ethyl                                   4-pyridylmethyl        CH.sub.3                                                                             OH      ethyl                                   3-pyridylmethyl        CH.sub.3                                                                             OH      ethyl                                   2-pyridylmethyl        CH.sub.3                                                                             OH      ethyl                                   benzyl                 CH.sub.3                                                                             OH      ethyl                                   4-HO.sub.2 C-benzyl    CH.sub.3                                                                             OH      ethyl                                   4-H.sub.2 NCO-benzyl   CH.sub.3                                                                             OH      ethyl                                   4-CH.sub.2 O-benzyl    CH.sub.3                                                                             OH      ethyl                                   4-HO-benzyl            CH.sub.3                                                                             OH      ethyl                                   4-R.sup.11 O-benzyl    CH.sub.3                                                                             OH      ethyl                                   4-Cl-benzyl            CH.sub.3                                                                             OH      ethyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             OH      ethyl                                   3-HO.sub.2 C-benzyl    CH.sub.3                                                                             OH      ethyl                                   3-H.sub.2 NCO-benzyl   CH.sub.3                                                                             OH      ethyl                                   3-CH.sub.3 O-benzyl    CH.sub.3                                                                             OH      ethyl                                   3-HO-benzyl            CH.sub.3                                                                             OH      ethyl                                   3-R.sup.11 O-benzyl    CH.sub.3                                                                             OH      ethyl                                   3-Cl-benzyl            CH.sub.3                                                                             OH      ethyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             OH      ethyl                                   2-HO.sub.2 C-benzyl    CH.sub.3                                                                             OH      ethyl                                   2-H.sub.2 NCO-benzyl   CH.sub.3                                                                             OH      ethyl                                   2-CH.sub.3 O-benzyl    CH.sub.3                                                                             OH      ethyl                                   2-HO-benzyl            CH.sub.3                                                                             OH      ethyl                                   2-R.sup.11 O-benzyl    CH.sub.3                                                                             OH      ethyl                                   2-Cl-benzyl            CH.sub.3                                                                             OH      ethyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             OH      ethyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             OH      ethyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             OH      ethyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             OH      ethyl                                   3-phenylimidazol-2-ylmethyl                                                                          CH.sub.3                                                                             OH      ethyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             OH      ethyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      ethyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      ethyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl-imidazol-2-ylmethyl                                                   CH.sub.3                                                                             OH      ethyl                                   3-(3-HO.sub.2 C-phenyl-imidazol-2-ylmethyl                                                           CH.sub.3                                                                             OH      ethyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             OH      ethyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      ethyl                                   3-(3-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(3-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      ethyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             OH      ethyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             OH      ethyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      ethyl                                   3-(2-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      ethyl                                   3-(2-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      ethyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             OH      ethyl                                   1-imidazolylmethyl     CH.sub.3                                                                             H       ethyl                                   2-imidazolylmethyl     CH.sub.3                                                                             H       ethyl                                   3-thiazolylmethyl      CH.sub.3                                                                             H       ethyl                                   2-thiazolylmethyl      CH.sub.3                                                                             H       ethyl                                   2-oxazolylmethyl       CH.sub.3                                                                             H       ethyl                                   5-tetrazolylmethyl     CH.sub.3                                                                             H       ethyl                                   4-pyridylmethyl        CH.sub.3                                                                             H       ethyl                                   3-pyridylmethyl        CH.sub.3                                                                             H       ethyl                                   2-pyridylmethyl        CH.sub.3                                                                             H       ethyl                                   benzyl                 CH.sub.3                                                                             H       ethyl                                   4-HO.sub.2 C-benzyl    CH.sub.3                                                                             H       ethyl                                   4-H.sub.2 NCO-benzyl   CH.sub.3                                                                             H       ethyl                                   4-CH.sub.3 O-benzyl    CH.sub.3                                                                             H       ethyl                                   4-HO-benzyl            CH.sub.3                                                                             H       ethyl                                   4-R.sup.11 O-benzyl    CH.sub.3                                                                             H       ethyl                                   4-Cl-benzyl            CH.sub.3                                                                             H       ethyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             H       ethyl                                   3-HO.sub.2 C-benzyl    CH.sub.3                                                                             H       ethyl                                   3-H.sub.2 NCO-benzyl   CH.sub.3                                                                             H       ethyl                                   3-CH.sub.3 O-benzyl    CH.sub.3                                                                             H       ethyl                                   3-HO-benzyl            CH.sub.3                                                                             H       ethyl                                   3-R.sup.11 O-benzyl    CH.sub.3                                                                             H       ethyl                                   3-Cl-benzyl            CH.sub.3                                                                             H       ethyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             H       ethyl                                   2-HO.sub.2 C-benzyl    CH.sub.3                                                                             H       ethyl                                   2-H.sub.2 NCO-benzyl   CH.sub.3                                                                             H       ethyl                                   2-CH.sub.3 O-benzyl    CH.sub.3                                                                             H       ethyl                                   2-HO-benzyl            CH.sub.3                                                                             H       ethyl                                   2-R.sup.11 O-benzyl    CH.sub.3                                                                             H       ethyl                                   2-Cl-benzyl            CH.sub.3                                                                             H       ethyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             H       ethyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             H       ethyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             H       ethyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             H       ethyl                                   3-phenylimidazol-2-ylmethyl                                                                          CH.sub.3                                                                             H       ethyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       ethyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             H       ethyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       ethyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       ethyl                                   3-(4-R.sup.11 O-phenyl-imidazol-2-ylmethyl                                                           CH.sub.3                                                                             H       ethyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       ethyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             H       ethyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       ethyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             H       ethyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       ethyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       ethyl                                   3-(3-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       ethyl                                   3-(3-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       ethyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             H       ethyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       ethyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             H       ethyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       ethyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       ethyl                                   3-(2-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       ethyl                                   3-(2-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       ethyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             H       ethyl                                   1-imidazolylmethyl     H      OH      ethyl                                   2-imidazolylmethyl     H      OH      ethyl                                   3-thiazolylmethyl      H      OH      ethyl                                   2-thiazolylmethyl      H      OH      ethyl                                   2-oxazolylmethyl       H      OH      ethyl                                   5-tetrazolylmethyl     H      OH      ethyl                                   4-pyridylmethyl        H      OH      ethyl                                   3-pyridylmethyl        H      OH      ethyl                                   2-pyridylmethyl        H      OH      ethyl                                   benzyl                 H      OH      ethyl                                   4-HO.sub.2 C-benzyl    H      OH      ethyl                                   4-H.sub.2 NCO-benzyl   H      OH      ethyl                                   4-CH.sub.3 O-benzyl    H      OH      ethyl                                   4-HO-benzyl            H      OH      ethyl                                   4-R.sup.11 O-benzyl    H      OH      ethyl                                   4-Cl-benzyl            H      OH      ethyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          H      OH      ethyl                                   3-HO.sub.2 C-benzyl    H      OH      ethyl                                   3-H.sub.2 NCO-benzyl   H      OH      ethyl                                   3-CH.sub.3 O-benzyl    H      OH      ethyl                                   3-HO-benzyl            H      OH      ethyl                                   3-R.sup.11 O-benzyl    H      OH      ethyl                                   3-Cl-benzyl            H      OH      ethyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          H      OH      ethyl                                   2-HO.sub.2 C-benzyl    H      OH      ethyl                                   2-H.sub.2 NCO-benzyl   H      OH      ethyl                                   2-CH.sub.3 O-benzyl    H      OH      ethyl                                   2-HO-benzyl            H      OH      ethyl                                   2-R.sup.11 O-benzyl    H      OH      ethyl                                   2-Cl-benzyl            H      OH      ethyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          H      OH      ethyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    H      OH      ethyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    H      OH      ethyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    H      OH      ethyl                                   3-phenylimidazol-2-ylmethyl                                                                          H      OH      ethyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      OH      ethyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      ethyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      ethyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      OH      ethyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      OH      ethyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      ethyl                                   3-(3-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(3-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      ethyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      OH      ethyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      OH      ethyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      ethyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      ethyl                                   3-(2-R.sup. 11 O-phenyl)-imidazol-2-ylmethyl                                                         H      OH      ethyl                                   3-(2-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      ethyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      OH      ethyl                                   1-imidazolylmethyl     H      H       ethyl                                   2-imidazolylmethyl     H      H       ethyl                                   3-thiazolylmethyl      H      H       ethyl                                   2-thiazolylmethyl      H      H       ethyl                                   2-oxazolylmethyl       H      H       ethyl                                   5-tetrazolylmethyl     H      H       ethyl                                   4-pyridylmethyl        H      H       ethyl                                   3-pyridylmethyl        H      H       ethyl                                   2-pyridylmethyl        H      H       ethyl                                   benzyl                 H      H       ethyl                                   4-HO.sub.2 C-benzyl    H      H       ethyl                                   4-H.sub.2 NCO-benzyl   H      H       ethyl                                   4-CH.sub.3 O-benzyl    H      H       ethyl                                   4-HO-benzyl            H      H       ethyl                                   4-R.sup.11 O-benzyl    H      H       ethyl                                   4-Cl-benzyl            H      H       ethyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          H      H       ethyl                                   3-HO.sub.2 C-benzyl    H      H       ethyl                                   3-H.sub.2 NCO-benzyl   H      H       ethyl                                   3-CH.sub.3 O-benzyl    H      H       ethyl                                   3-HO-benzyl            H      H       ethyl                                   3-R.sup.11 O-benzyl    H      H       ethyl                                   3-Cl-benzyl            H      H       ethyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          H      H       ethyl                                   2-HO.sub.2 C-benzyl    H      H       ethyl                                   2-H.sub.2 NCO-benzyl   H      H       ethyl                                   2-CH.sub.3 O-benzyl    H      H       ethyl                                   2-HO-benzyl            H      H       ethyl                                   2-R.sup.11 O-benzyl    H      H       ethyl                                   2-Cl-benzyl            H      H       ethyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          H      H       ethyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    H      H       ethyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    H      H       ethyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    H      H       ethyl                                   3-phenylimidazol-2-ylmethyl                                                                          H      H       ethyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      H       ethyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      H       ethyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      H       ethyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      H       ethyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      H       ethyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      H       ethyl                                   3-(3-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(3-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      H       ethyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      H       ethyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      H       ethyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      H       ethyl                                   3-(2-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       ethyl                                   3-2-Cl-phenyl)-imidazol-2-ylmethyl                                                                   H      H       ethyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      H       ethyl                                   1-imidazolylmethyl     CH.sub.3                                                                             OH      allyl                                   2-imidazolylmethyl     CH.sub.3                                                                             OH      allyl                                   3-thiazolylmethyl      CH.sub.3                                                                             OH      allyl                                   2-thiazolylmethyl      CH.sub.3                                                                             OH      allyl                                   2-oxazolylmethyl       CH.sub.3                                                                             OH      allyl                                   5-tetrazolylmethyl     CH.sub.3                                                                             OH      allyl                                   4-pyridylmethyl        CH.sub.3                                                                             OH      allyl                                   3-pyridylmethyl        CH.sub.3                                                                             OH      allyl                                   2-pyridylmethyl        CH.sub.3                                                                             OH      allyl                                   benzyl                 CH.sub.3                                                                             OH      allyl                                   4-HO.sub.2 C-benzyl    CH.sub.3                                                                             OH      allyl                                   4-H.sub.2 NCO-benzyl   CH.sub.3                                                                             OH      allyl                                   4-CH.sub.3 O-benzyl    CH.sub.3                                                                             OH      allyl                                   4-HO-benzyl            CH.sub.3                                                                             OH      allyl                                   4-R.sup.11 O-benzyl    CH.sub.3                                                                             OH      allyl                                   4-Cl-benzyl            CH.sub.3                                                                             OH      allyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             OH      allyl                                   3-HO.sub.2 C-benzyl    CH.sub.3                                                                             OH      allyl                                   3-H.sub.2 NCO-benzyl   CH.sub.3                                                                             OH      allyl                                   3-CH.sub.3 O-benzyl    CH.sub.3                                                                             OH      allyl                                   3-HO-benzyl            CH.sub.3                                                                             OH      allyl                                   3-R.sup.11 O-benzyl    CH.sub.3                                                                             OH      allyl                                   3-Cl-benzyl            CH.sub.3                                                                             OH      allyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             OH      allyl                                   2-HO.sub.2 C-benzyl    CH.sub.3                                                                             OH      allyl                                   2-H.sub.2 NCO-benzyl   CH.sub.3                                                                             OH      allyl                                   2-CH.sub.3 O-benzyl    CH.sub.3                                                                             OH      allyl                                   2-HO-benzyl            CH.sub.3                                                                             OH      allyl                                   2-R.sup.11 O-benzyl    CH.sub.3                                                                             OH      allyl                                   2-Cl-benzyl            CH.sub.3                                                                             OH      allyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             OH      allyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             OH      allyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             OH      allyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             OH      allyl                                   3-phenylimidazol-2-ylmethyl                                                                          CH.sub.3                                                                             OH      allyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             OH      allyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      allyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      allyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             OH      allyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             OH      allyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      allyl                                   3-(3-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub. 3                                                                            OH      allyl                                   3-(3-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      allyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             OH      allyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             OH      allyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      allyl                                   3-(2-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             OH      allyl                                   3-(2-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             OH      allyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             OH      allyl                                   1-imidazolylmethyl     CH.sub.3                                                                             H       allyl                                   2-imidazolylmethyl     CH.sub.3                                                                             H       allyl                                   3-thiazolylmethyl      CH.sub.3                                                                             H       allyl                                   2-thiazolylmethyl      CH.sub.3                                                                             H       allyl                                   2-oxazolylmethyl       CH.sub.3                                                                             H       allyl                                   5-tetrazolylmethyl     CH.sub.3                                                                             H       allyl                                   4-pyridylmethyl        CH.sub.3                                                                             H       allyl                                   3-pyridylmethyl        CH.sub.3                                                                             H       allyl                                   2-pyridylmethyl        CH.sub.3                                                                             H       allyl                                   benzyl                 CH.sub.3                                                                             H       allyl                                   4-HO-.sub.2 C-benzyl   CH.sub.3                                                                             H       allyl                                   4-H.sub.2 NCO-benzyl   CH.sub.3                                                                             H       allyl                                   4-CH.sub.3 O-benzyl    CH.sub.3                                                                             H       allyl                                   4-HO-benzyl            CH.sub.3                                                                             H       allyl                                   4-R.sup.11 O-benzyl    CH.sub.3                                                                             H       allyl                                   4-Cl-benzyl            CH.sub.3                                                                             H       allyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             H       allyl                                   3-HO.sub.2 C-benzyl    CH.sub.3                                                                             H       allyl                                   3-H.sub.2 NCO-benzyl   CH.sub.3                                                                             H       allyl                                   3-CH.sub.3 O-benzyl    CH.sub.3                                                                             H       allyl                                   3-HO-benzyl            CH.sub.3                                                                             H       allyl                                   3-R.sup.11 O-benzyl    CH.sub.3                                                                             H       allyl                                   3-Cl-benzyl            CH.sub.3                                                                             H       allyl                                   3-(CH.sub.3 ).sub.2 N-benzyl                                                                         CH.sub.3                                                                             H       allyl                                   2-HO.sub.2 C-benzyl    CH.sub.3                                                                             H       allyl                                   2-H.sub.2 NCO-benzyl   CH.sub.3                                                                             H       allyl                                   2-CH.sub.3 O-benzyl    CH.sub.3                                                                             H       allyl                                   2-HO-benzyl            CH.sub.3                                                                             H       allyl                                   2-R.sup.11 O-benzyl    CH.sub.3                                                                             H       allyl                                   2-Cl-benzyl            CH.sub.3                                                                             H       allyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          CH.sub.3                                                                             H       allyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             H       allyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             H       allyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    CH.sub.3                                                                             H       allyl                                   3-phenylimidazol-2-ylmethyl                                                                          CH.sub.3                                                                             H       allyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             H       allyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       allyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       allyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             H       allyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             H       allyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       allyl                                   3-(3-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(3-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       allyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             H       allyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         CH.sub.3                                                                             H       allyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       allyl                                   3-(2-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          CH.sub.3                                                                             H       allyl                                   3-(2-Cl-phenyl)-imidazol-2-ylmethyl                                                                  CH.sub.3                                                                             H       allyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  CH.sub.3                                                                             H       allyl                                   1-imidazolylmethyl     H      OH      allyl                                   2-imidazolylmethyl     H      OH      allyl                                   3-thiazolylmethyl      H      OH      allyl                                   2-thiazolylmethyl      H      OH      allyl                                   2-oxazolylmethyl       H      OH      allyl                                   5-tetrazolylmethyl     H      OH      allyl                                   4-pyridylmethyl        H      OH      allyl                                   3-pyridylmethyl        H      OH      allyl                                   2-pyridylmethyl        H      OH      allyl                                   benzyl                 H      OH      allyl                                   4-HO.sub.2 C-benzyl    H      OH      allyl                                   4-H.sub.2 NCO-benzyl   H      OH      allyl                                   4-CH.sub.3 O-benzyl    H      OH      allyl                                   4-HO-benzyl            H      OH      allyl                                   4-R.sup.11 O-benzyl    H      OH      allyl                                   4-Cl-benzyl            H      OH      allyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          H      OH      allyl                                   3-HO.sub.2 C-benzyl    H      OH      allyl                                   3-H.sub.2 NCO-benzyl   H      OH      allyl                                   3-CH.sub.3 O-benzyl    H      OH      allyl                                   3-HO-benzyl            H      OH      allyl                                   3-R.sup.11 O-benzyl    H      OH      allyl                                   3-Cl-benzyl            H      OH      allyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          H      OH      allyl                                   2-HO.sub.2 C-benzyl    H      OH      allyl                                   2-H.sub.2 NCO-benzyl   H      OH      allyl                                   2-CH.sub.3 O-benzyl    H      OH      allyl                                   2-HO-benzyl            H      OH      allyl                                   2-R.sup.11 O-benzyl    H      OH      allyl                                   2-Cl-benzyl            H      OH      allyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          H      OH      allyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    H      OH      allyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    H      OH      allyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    H      OH      allyl                                   3-phenylimidazol-2-ylmethyl                                                                          H      OH      allyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      OH      allyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      allyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      allyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      OH      allyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      OH      allyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      allyl                                   3-(3-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(3-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      allyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      OH      allyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      OH      allyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      allyl                                   3-(2-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      OH      allyl                                   3-(2-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      OH      allyl                                   3-(2-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      OH      allyl                                   1-imidazolylmethyl     H      H       allyl                                   2-imidazolylmethyl     H      H       allyl                                   3-thiazolylmethyl      H      H       allyl                                   2-thiazolylmethyl      H      H       allyl                                   2-oxazolylmethyl       H      H       allyl                                   5-tetrazolylmethyl     H      H       allyl                                   4-pyridylmethyl        H      H       allyl                                   3-pyridylmethyl        H      H       allyl                                   2-pyridylmethyl        H      H       allyl                                   benzyl                 H      H       allyl                                   4-HO.sub.2 C-benzyl    H      H       allyl                                   4-H.sub.2 NCO-benzyl   H      H       allyl                                   4-CH.sub.3 O-benzyl    H      H       allyl                                   4-HO-benzyl            H      H       allyl                                   4-R.sup.11 O-benzyl    H      H       allyl                                   4-Cl-benzyl            H      H       allyl                                   4-(CH.sub.3).sub.2 N-benzyl                                                                          H      H       allyl                                   3-HO.sub.2 C-benzyl    H      H       allyl                                   3-H.sub.2 NCO-benzyl   H      H       allyl                                   3-CH.sub.3 O-benzyl    H      H       allyl                                   3-HO-benzyl            H      H       allyl                                   3-R.sup.11 O-benzyl    H      H       allyl                                   3-Cl-benzyl            H      H       allyl                                   3-(CH.sub.3).sub.2 N-benzyl                                                                          H      H       allyl                                   2-HO.sub.2 C-benzyl    H      H       allyl                                   2-H.sub.2 NCO-benzyl   H      H       allyl                                   2-CH.sub.3 O-benzyl    H      H       allyl                                   2-HO-benzyl            H      H       allyl                                   2-R.sup.11 O-benzyl    H      H       allyl                                   2-Cl-benzyl            H      H       allyl                                   2-(CH.sub.3).sub.2 N-benzyl                                                                          H      H       allyl                                   3-(4-pyridyl)-imidazol-2-ylmethyl                                                                    H      H       allyl                                   3-(3-pyridyl)-imidazol-2-ylmethyl                                                                    H      H       allyl                                   3-(2-pyridyl)-imidazol-2-ylmethyl                                                                    H      H       allyl                                   3-phenylimidazol-2-ylmethyl                                                                          H      H       allyl                                   3-(4-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(4-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      H       allyl                                   3-(4-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(4-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      H       allyl                                   3-(4-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(4-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      H       allyl                                   3-(4-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      H       allyl                                   3-(3-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(3-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      H       allyl                                   3-(3-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(3-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      H       allyl                                   3-(3-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(3-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      H       allyl                                   3-(3-(CH.sub.3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                  H      H       allyl                                   3-(2-HO.sub.2 C-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(2-H.sub.2 NCO-phenyl)-imidazol-2-ylmethyl                                                         H      H       allyl                                   3-(2-CH.sub.3 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(2-HO-phenyl)-imidazol-2-ylmethyl                                                                  H      H       allyl                                   3-(2-R.sup.11 O-phenyl)-imidazol-2-ylmethyl                                                          H      H       allyl                                   3-(2-Cl-phenyl)-imidazol-2-ylmethyl                                                                  H      H       allyl                                   3-(2-(CH.sub. 3).sub.2 N-phenyl)-imidazol-2-ylmethyl                                                 H      H       allyl.                                  ______________________________________                                    


9. A compound which is selected from the group consistingof:17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-furanyl)methoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-furanyl)methoxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(2-furanyl)methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-thiophene)methoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3-thiophene)methoxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(3-thiophene)methoxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(2-thiophene)methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-(3-thiophene)methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-thiophene)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(2-benzothienyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1-hydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14,20-trihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,20-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1-hydroxy-12-[2'-(4"-(5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,20-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-n-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-n-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-methyl-5-indolyl)oxy-3"-i-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,20-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1-hydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)-oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-ethyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetranone;17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,20-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)-oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1-hydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)-oxy-3"-methoxycyclohexyl-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-propyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,20-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1-hydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-allyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-2-hydroxyethyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,20-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14,20-trihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,20-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1-hydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-benzyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-hydroxyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1,14-dihydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1-hydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Allyl-1-hydroxy-12-[2'-(4"-(1-N-cyclopropyl-5-indolyl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1-hydroxy-12-[2'-(4"-methoxy-N-tryptophanylcarbonylmethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1-hydroxy-12-[2'-(4"-3-indolylethylaminocarbonylmethoxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-(3-hydroxypropyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(3"-hydroxy-4"-(1-hydroxyethylindol-5-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-hydroxyethylindol-6-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methylindol-6-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-dibenzylphosphonoxy-ethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone; Monopotassium salt of17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-phosphonoxy-ethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]-octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-(N,N-dimethylglycyloxy)ethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-succinyloxyethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methyl-3-phenylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1-methyl-3-(2-hydroxyethyl)indol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1,3-dimethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1,3-dimethylindol-5-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(9'-methylcarbazol-3'-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-diethylaminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-dimethylaminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-aminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(3'""-benzyloxycarbonyl-2'""-benzyloxycarbonylaminopropionyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(aspartyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(1'""-imidazolylcarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-((2""-(1'""-piperazinocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(2'""-hydroy)ethylaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(isopropyaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(1'""-piperidinocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(1'""-morphilinocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(diphenylaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-(diethylaminocarbonyloxy)ethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-methanesulfonyloxyethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-azidoethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-(2""-aminoethyl)indol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-t-butyldimethylsilyloxyethoxyethylindol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(4"-(1'"-hydroxyethoxyethylindol-5'"-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;17-Ethyl-1,14-dihydroxy-12-[2'-(3"-methoxy-4"-(1'"-(1""-oxoprop-3""-yl)indol-5'"-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone; and17-Ethyl-1,14-dihydroxy-12-[2'-(3"-methoxy-4"-(1'"-(1""-carboxyeth-2""-yl)indol-5'"-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0⁴,9]octacos-18-ene-2,3,10,16-tetraone;
 10. A compound which is: ##STR40##or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areselected from the following combinations of substituents:

    ______________________________________                                        R.sup.1                   R.sup.2                                             ______________________________________                                        (a)                                                                                   ##STR41##             CH.sub.3                                        (b)                                                                                   ##STR42##             H                                               (c)                                                                                   ##STR43##             CH.sub.3                                        (d)                                                                                   ##STR44##             CH.sub.3                                        (e)                                                                                   ##STR45##             CH.sub.3                                        (f)                                                                                   ##STR46##             H                                               (g)                                                                                   ##STR47##             H                                               (h)                                                                                   ##STR48##             H                                               (i)                                                                                   ##STR49##             CH.sub.3                                        (j)                                                                                   ##STR50##             H                                               (k)                                                                                   ##STR51##             CH.sub.3                                        (l)                                                                                   ##STR52##             H                                               (m)                                                                                   ##STR53##             CH.sub.3                                        (n)                                                                                   ##STR54##             H                                               (o)                                                                                   ##STR55##             CH.sub.3                                        (p)                                                                                   ##STR56##             H                                               ______________________________________                                    


11. The compound of claim 10 which is: ##STR57##
 12. The compound ofclaim 10 which is: ##STR58##
 13. The compound of claim 10 which is:##STR59##
 14. The compound of claim 10 which is: ##STR60##
 15. Thecompound of claim 10 which is: ##STR61##
 16. The compound of claim 10which is: ##STR62##
 17. The compound of claim 10 which is: ##STR63##